Category Archives: News

President’s Message: Looking Forward

Thomas Davis, MD

Welcome to 2023!  Each new year is a chance to put into perspective the past year, and begin anew with plans to build upon the foundation laid by our predecessors.

Harry Gould, MD, our immediate past president, with the help of our board, Lori Postal our executive director, our vendors, sponsors, and speakers have been able to guide us through perhaps the most turbulent period in Southern Pain Society’s 36 years. The last three years with Covid 19 and a rapidly changing healthcare landscape presented unprecedented challenges.

The Southern Pain Society’s annual meeting in New Orleans, “Pain Management: The Times They Are Still A-Changin’”, in October 2022, was our first live meeting in over 2 years. This meeting helped to reaffirm the importance of in-person collaboration. In a healthcare environment which is often demeaning and confrontational, with record burnout and colleagues who have lost their lives, SPS and the other societies of likeminded individuals can make a more hopeful existence and perhaps refocus where our focus should be: helping those who are suffering in pain.

How do we build an even more successful Southern Pain Society? I believe the seeds for greater involvement and proliferation of pain education have already been sown. This past meeting saw our largest number of residents, fellows, and student involvement with research abstracts. In no small part, was this due to the mentoring by board members such as Alethia Sellers, MD and Casey Murphy, MD.  Hopefully, we may see a greater number of mentors involved from other institutions throughout the south. Board member Norman Harden, MD, has been able to use an abundant and varied research background to offer peer review guidance, and plant yet another seed for greater involvement with the investigation of pain.

During the peak of Covid we were able to launch a YouTube channel, and maintain Facebook and social media presence. These outreaches are in their infancy but hopefully will grow with board and SPS members, speakers, and vendor support.

Our finance committee under Treasurer Randy Roig, MD, and President elect James Weisberg, PhD, continue to offer a steady hand in an environment not always friendly to non- profit societies. Our Secretary, Eric Royster, MD has utilized his breadth of abilities from conference committees and local knowledge of pain providers in Louisiana, to offer talks on interventional pain. All of these volunteers, plus the past presidents and board members, help to keep SPS vibrant. To those who are not involved but who are reading this, please consider joining us.

SPS has been successful because of our diversity of interests and practices, and because we acknowledge pain and that the treatment of the individual takes a community. I am hopeful that the forces that limit helping our patients can be minimized. To help these patients we need everyone to join us: students, residents, fellows, psychologists, nurses, interventionists, anesthesiologists, psychiatrists, orthopedists, sports medicine, neurosurgeons, physiatrists, rheumatologists, neurologists, primary care, dentists, physical and occupation therapists, chiropractors, pharmacists, researchers, vendors and sponsors, patient advocates and the family caregivers in the 18 states and territories that make up our Society.

 (Proposed) World Headache Society’s Definition for Refractory Migraine

Lawrence Robbins, MD


To expand the current description of refractory migraine, the World Headache Society advocates the use of both simple and complex definitions. Simple would be for the general use of patients and support groups, and complex for research and clinical purposes. These definitions include the roles of preventive and abortive medications, non-medication treatments, medication overuse headache (MOH), and a refractory scale to rate severity.  The complex definition provides criteria for the categorization of responses to both abortives and preventives based on the availability of migraine treatments in different countries. It is suggested that refractoriness is defined as failure of adequate trials of at least 3 classes of preventives or 2 classes of abortives.  For countries with limited access to both preventive and abortive therapies, the patient should have failed at least half of the available preventive classes, or all of the classes of the available abortive therapies. The rationale behind the definitions is discussed in the subsequent sections.

A. Introduction

When an individual has persistent headaches that fail to improve after a trial of the standard treatments, the term “refractory migraine” is often used in clinical practice.1   This term was coined by Reisman in 1952.2 Since then, a number of definitions for refractory migraines have been proposed.3,4,5,6,7 However, the current definition is appropriate primarily for countries where there is a wide array of treatments available, including onabotulinumtoxinA and CGRP medications. There is no mention in the current definitions of abortive approaches. Moreover, the role of medication overuse headache (MOH) is unclear in current definitions. There is no scale to separate milder patients from the more severe refractory migraineurs. It is also noted that current definitions focus on refractory chronic migraine. We have chosen to define refractory migraine.

This paper outlines the proposed definition of refractory migraine and the rationale behind the definition. In addition, other topics such as abortive medications, MOH, and a refractory scale have been included. To expand the current definition of refractory migraine, we would like to suggest both simple and complex definitions. Simple would be for easy general use, and complex for research and headache specialists. In the future, a panel of headache experts from the regional directorates of the World Headache Society will publish a consensus document.

B. Objectives for a revised definition

 To standardize terminology and agree on working definitions in order to:
– provide a clear definition of refractory migraines for:

  1. Headache specialists
  2. Researchers in headache medicine
  3. All clinicians and allied healthcare professionals
  4. Patients and caregivers
  5. Policy makers and patient advocacy groups

– classify headaches in terms of severity and disability across the lifespan (pediatric, adult, elderly)
-to include responses to abortives as well as preventive therapies

C. Definition of Refractory Migraine

Simple definition:
The migraines have not been adequately controlled by medications or non-medication approaches.

Note: This definition is drafted for the general use of patients, primary caregivers and patient advocate groups.

Complex definition:
The migraines have not been adequately controlled by medications or non-medication approaches (non-pharmacological). 8,9    

The migraines may be refractory to preventives, abortives, or to both. Not all patients have required preventive medications. If they have only been taking abortives, but these have failed, they do have refractory migraine (but just to abortive therapies). In addition, MOH will have been addressed prior to designating the patient as having refractory migraine.

Migraine is defined according to the International Classification of Headache Disorders-3.  In addition, migraine mimics and secondary migraines have been excluded,  as discussed in the World Headaches Society’s WHIS-MCH1 Classification Group 1, Syndrome of Migraine.

Note: This definition is drafted for the use of clinicians, allied medical professionals, and researchers in the field of headache medicine.

 Explanatory Notes

 2.1 Non- medication approaches

 Non-medication approaches have failed to achieve adequate relief. Not all patients are able to utilize most of the non-medication therapies, but attention to the usual lifestyle changes should have been attempted. At least one of the following measures should have been utilized: meditation, biofeedback, other relaxation approaches, psychotherapy, yoga, acupuncture, massage, physical therapy, and others.10,11,12

 2.2 Preventive medications or preventive injections

For patients who have had access to almost all migraine medications, including OnabotulinumtoxinA and CGRP monoclonal antibodies:      

The preventive approaches have failed to reduce the impact of the migraines by at least 50%, as evidenced by a headache diary.13,14 The patient should have failed on at least 3 classes of migraine preventives.

Failure was either inadequate relief from an adequate trial of the medication for at least 8 to 12 weeks or discontinuation due to adverse effects or ineligibility due to co-morbidities. The classes of preventives include (certain) anticonvulsants, antidepressants, and antihypertensives. In addition, the patient will have failed on onabotulinumtoxinA and/or a CGRP preventive (injection or oral).

Preventive medications: For patients with limited access to certain migraine medications

The preventive approaches have failed to reduce the impact of the migraines by at least 50%.  The patient should have failed on at least half the classes of migraine preventives that are available. Failure was either inadequate relief from an adequate trial of the medication for at least 8 to 12 weeks, or discontinuation due to adverse effects. The classes of preventives include (certain) anticonvulsants, antidepressants, and antihypertensives. In addition, the patient will have failed on onabotulinum toxin A and/or a CGRP preventive (injection or oral), or trials of non-medication therapies such as non-invasive neuromodulation, acupuncture, yoga or CBT.

 2.3 Abortive therapies

Abortive therapies: For patients who have access to almost all abortives, including gepants

The abortives have not provided consistent relief at least 50% of the time (trial in at least 4 consecutive headaches). Relief is defined as pain-freedom (or “near” pain-freedom) at 2 hours, after medication overuse headache has been addressed. 15,16,18 Alternatively the medication may have been discontinued due to intolerable adverse effects. The patient should have utilized simple analgesics (paracetamol and NSAIDs) and at least 2 of the following categories: triptans, gepants, DHE, or injectables (ketorolac, etc).

Abortive therapies: For patients with limited access to certain abortive medications.    

Refractoriness may be defined as non-responsiveness to all of the available classes of abortive therapies.

NOTE: It is important to note if the patient is refractory to preventives, abortives, or both preventives and abortives.

 2.4 The Role of Medication Overuse Headache (MOH)

Medication overuse headache (MOH): The patient should have been assessed for MOH. MOH is defined according to ICHD-3 with the modifications as follows:

  1. It is important that MOH not be conflated or confused with medication overuse (MO)
  2. To determine whether MOH is truly present, a careful history regarding the offending medication must be obtained. Based on the history and assessment of headache diaries, it should be more likely than not that the offending medication is actually triggering more migraines. Ideally, the subsequent medication should be withdrawn, and the effect on the patient’s migraines observed. This is not always possible.
  3. After observing the results of the offending medication having been discontinued, a definite determination of MOH may be made. If it is determined that the patient is most likely is suffering from MOH, the designation of refractory migraine will be withheld until the MOH situation is resolved.

2.5 Refractory Migraine Rating Scale:

It is useful to separate patients into mild, moderate, and severe refractory. This is helpful for research purposes. In addition, our clinical approach and expectations are different for a patient with mild refractory migraine versus severe refractory migraine.18,19

Refractory Rating Scale for adult patients, age 20+:  The scale consists of eight items, with 10 possible points. Points are added if the patient is:

Refractory to preventive approaches

2 points

Refractory to abortive medications

2 points

Duration (number of years) of migraine occurrence; if greater than 10 years

1 point

Number of headaches per month; if 25 or more days, on average

1 point

Two or more diagnosed comorbid central sensitization syndromes (irritable bowel syndrome [IBS], chronic regional pain syndrome (CRPS), temporomandibular joint disorder [TMD], fibromyalgia, chronic pelvic pain, burning mouth syndrome); in addition: chronic fatigue syndrome, or visual snow

1 point

 Psychiatric comorbidities, whether a severe Axis I disorder (ie, an affective disorder) or any definite Axis II disorder (ie, a personality disorder), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)

1 point

Disability (work/school and/or home )

1 point

Medication overuse headache (not simply medication overuse)

1 point

After totaling the points, the scale helps clinicians to categorize patients as follows:
2 to 4 points= mild refractory migraine
5 to 7 points= moderate refractory migraine
8 to 10 points= severe refractory migraine.

Refractory Migraine Rating Scale for Adolescents, ages 11 to 19:

 The point system for the adolescent patient would be as follows:

Refractory to preventives (which may include onabotulinumtoxinA)

1 point

Refractory to abortives

1 point

Headache occurrence greater than one year

1 point

Number of headaches per month; if 25 or more days, on average

1 point

Significant comorbidities; if at least one is present (IBS, TMD, fibromyalgia, or chronic fatigue)

1 point

Psychiatric comorbidities: severe Axis I (affective disorders), or a strong indication that Axis II (personality disorders) may be present

1 point

Disability defined as an inability to go to school for at least 2 months due to headache (either homebound, or a greatly modified schedule), or a significant decrease in functioning

1 point

Severe family dysfunction, which may include personality disorder pathology in the primary parent (usually the mother)

1 point

With this scale, a total of 8 points would be possible, ranking as such:

   2 to 4 points = mild refractory migraine.
   5 to 6 points = moderate refractory migraine.                         
   7 to 8 points = severe refractory migraine.

Future Perspectives and Conclusion

This is a continuous work in progress. We have attempted to revise and add to existing refractory definitions. Our primary changes include: including abortives in a refractory definition, separating a simple from a more complex definition, adding a section that applies to patients with limited access to more advanced approaches, adding to the existing MOH definition, and adding a refractory rating scale for adults and adolescents.

In the future, we may use biomarkers to identify refractory patients, but until then we must use our clinical criteria.

Key points


Simple Definition

The migraines have not been adequately controlled by medications or non-medication approaches.  

Complex Definition of Refractory Migraine

>The migraines have not been adequately controlled. Non-medication approaches had not sufficiently alleviated the headaches. It is important to note if the patient is refractory to preventives, abortives, or both. Not all patients will have required preventive therapies.

>If preventives have been used, they have failed to reduce the impact of the migraines by at least 50%. At least 3 classes of preventives will have had an adequate trial.

>Abortive medications will have failed to achieve adequate relief of 50% for at least 4 episodes.

>Medication overuse headache will have been adequately addressed.

>For countries with limited access to both preventive and abortive therapies, the patient should have failed at least half of the available preventive classes or all of the classes of the available abortives.


Committee Chair: Dr. Lawrence Robbins

Members: Dr. Pravin Thomas, Dr. Paul Emmanuel Yambao

Permission has been obtained from the co-authors to reproduce this article on Refractory Headache definition in the SPS newsletter.  Dr. Thomas is the founder (and directs) of the WHS, and Dr. Robbins is a Vice President. The permission comes from Dr. Pravin Thomas. 


  1. D’Antona, L., Matharu, M. Identifying and managing refractory migraine: barriers and opportunities?. J Headache Pain 20, 89 (2019).
  2. Reisman EE Jr (1952) The use of experimental suppositories in treating refractory migraine. Am Pract Dig Treat 3(4):308–310
  3. Sacco, S., Braschinsky, M., Ducros, A. et al. European headache federation consensus on the definition of resistant and refractory migraine. J Headache Pain 21, 76 (2020).
  4. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D (2006) Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia 26:1168–1170
  5. Martelletti P, Katsarava Z, Lampl C, Magis D, Bendtsen L, Negro A, Russell MB, Mitsikostas DD, Jensen RH (2014) Refractory chronic migraine: a consensus statement on clinical definition from the European headache federation. J Headache Pain 15:47
  6. Schulman EA, Lake AE 3rd, Goadsby PJ, Peterlin BL, Siegel SE, Markley HG, Lipton RB (2008) Defining refractory migraine and refractory chronic migraine: proposed criteria from the refractory headache special interest section of the American headache society. Headache 48:778–782
  7. Wöber C, Wessely P, Austrian Consensus Group on Refractory Chronic Migraine (2014) Comment on: Martelletti et al. Refractory chronic migraine: a consensus statement on clinical definition from the European Headache Federation. J H
  8. Guidelines /ICHD – International Headache Society (
  9. Classification of Head, Neck, and Face Pains First Edition (WHS-MCH1): Position paper of the WHS Classification Committee (
  10. Grazzi L, Toppo C, D’Amico D, Leonardi M, Martelletti P, Raggi A, Guastafierro E. Non-Pharmacological Approaches to Headaches: Non-Invasive Neuromodulation, Nutraceuticals, and Behavioral Approaches. Int J Environ Res Public Health. 2021 Feb 5;18(4):1503. doi: 10.3390/ijerph18041503. PMID: 33562487; PMCID: PMC7914516
  11. Wu Q, Liu P, Liao C, Tan L. Effectiveness of yoga therapy for migraine: a meta-analysis of randomized controlled studies. J Clin Neurosci. 2022.
  12. Ou MQ, Fan WH, Sun FR, Jie WX, Lin MJ, Cai YJ, Liang SY, Yu YS, Li MH, Cui LL, Zhou HH. A Systematic Review and Meta-analysis of the Therapeutic Effect of Acupuncture on Migraine. Front Neurol. 2020 Jun 30;11:596. doi: 10.3389/fneur.2020.00596. PMID: 32714268; PMCID: PMC7344239.
  13. Silberstein SD. Preventive Migraine Treatment. Continuum (Minneap Minn). 2015 Aug;21(4 Headache):973-89. doi: 10.1212/CON.0000000000000199. PMID: 26252585; PMCID: PMC4640499.
  14. Baos V, Ester F, Castellanos A, Nocea G, Caloto MT, Gerth WC; I-Max Study Group. Use of a structured migraine diary improves patient and physician communication about migraine disability and treatment outcomes. Int J Clin Pract. 2005 Mar;59(3):281-6. doi: 10.1111/j.1742-1241.2005.00469.x. PMID: 15857323.
  15. Silberstein SD, Newman LC, Marmura MJ, Nahas SJ, Farr SJ. Efficacy endpoints in migraine clinical trials: the importance of assessing freedom from pain. Curr Med Res Opin. 2013 Jul;29(7):861-7. doi: 10.1185/03007995.2013.787980. Epub 2013 May 22. PMID: 23514092.
  16. Tfelt-Hansen P, Diener HC. Pain freedom after 2 hours should be the primary outcome in controlled trials treating migraine attacks. Cephalalgia. 2020 Oct;40(12):1331-1335. doi: 10.1177/0333102420941827. Epub 2020 Jul 13. PMID: 32660268.
  17. VanderPluym JH, Halker Singh RB, Urtecho M, et al. Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis. 2021;325(23):2357–2369. doi:10.1001/jama.2021.7939A
  18. Sacco, S., Lampl, C., Amin, F.M. et al. European Headache Federation (EHF) consensus on the definition of effective treatment of a migraine attack and of triptan failure. J Headache Pain 23, 133 (2022).
  19. Robbins L. Refractory chronic migraine: long-term follow-up using a refractory rating scale. J Headache Pain. 2012 Apr;13(3):225-9. doi: 10.1007/s10194-012-0423-z. Epub 2012 Feb 25. PMID: 22367626; PMCID: PMC3311833.
  20. Robbins L. Refractory Chronic Migraine: Mild, Moderate, or Severe. Pract Pain Manag. 2019;19(4).
  21. Safiri, Saeida,b; Pourfathi, Hojjatc; Eagan, Arielled,e; Mansournia, Mohammad Alif; Khodayari, Mohammad Taghig; Sullman, Mark J.M.h,i; Kaufman, Jayj; Collins, Garyk,l; Dai, Haijiangm; Bragazzi, Nicola Luigim; Kolahi, Ali-Asgharn,*. Global, regional, and national burden of migraine in 204 countries and territories, 1990 to 2019. PAIN: February 2022 – Volume 163 – Issue 2 – p e293-e309 doi: 10.1097/j.pain.0000000000002275


Refractory Head, Neck, and Facial Pain due to Cervicomedullary-Junction Glioma Relieved with Sphenopalatine Ganglion Blockade

Wilkinson, A.J., Ege, E., Osborne, A., Driver, L., Chai, T.


The management of head, neck, and facial pain due to oncologic origin in patients is difficult and often undertreated. Many patients experience pain refractory to common treatment modalities, both non-interventional and interventional.1, 3 The sphenopalatine ganglion (SPG) is considered to be the autonomic hub of the skull, with association with the sensory nerve fibers of the maxillary nerve. Blockade of the SPG has been previously shown to be useful in headache syndromes and is considered safe and minimally invasive.1 Yet, there is limited literature on the use of SPG blockade for head, neck, and facial pain due to oncologic origin.1, 2, 3 We present the successful use of sphenopalatine ganglion blockade for the treatment of refractory head, neck, and facial pain of oncologic origin.


In highly prevalent head and neck cancer, pain is difficult to manage, with many patients failing conventional treatment with oral analgesics and adjuvant therapies.1, 3 Interventional techniques can be beneficial to treat such patients. The association of the sphenopalatine ganglion (SPG) with the maxillary nerve sensory fibers makes it an area of interest in treating pain in this population. The SPG blocks can be used to treat the pain of the hard and soft palate tonsils, nasal cavities, paranasal sinuses, oral gingiva, premaxillary soft tissue maxilla, and orbital floor.1 We present the successful use of an SPG nerve block for the treatment of head and neck cancer pain due to a cervicomedullary-junction glioma. 

 Case Report

A 62-year-old male with an oncologic history of a cervicomedullary-junction glioma status post proton therapy presented to the clinic due to a severe, persistent headache, skull base/neck pain, and left-sided facial pain. (Figure 1) Multiple treatment modalities were attempted in this patient, including multi-modal pain therapies and opioids. The patient also failed to respond to other interventional treatments including occipital nerve blocks, cervical facet joint injections, onabotulinum-A toxin chemodenervation of the craniofacial muscles, ketamine infusions, and intrathecal trials with opioids and ziconotide. After the failure of these above treatments, he was deemed a candidate for a sphenopalatine ganglion blockade for refractory pain. 

He later underwent a left-sided sphenopalatine ganglion (SPG) block via a transnasal approach utilizing a catheter designed specifically for the procedure.4 He was placed in a supine position with his neck slightly extended. The tip of the catheter was advanced intranasally through the left nostril, superior to the middle nasal turbinate. 1.5 ml of 2% viscous lidocaine was injected, flowing toward the nasal mucosa overlying the SPG. Afterward, the patient’s position was held for five minutes. He reported substantial pain relief which was not felt with any of his other previously discussed treatment modalities. This relief lasted for several weeks, prompting the patient to undergo repeated, monthly SPG blocks. 


The sphenopalatine ganglion (SPG) is considered the autonomic hub within the skull. The SPG is located within the pterygopalatine fossa, and numerous sympathetic and parasympathetic fibers synapse at or course through the ganglion.1 The SPG blockade, considered safe and minimally invasive, can be performed via transnasal, infrazygomatic or transoral approaches.1, 5 Based on the highest level of evidence available, the SPG blockade is indicated for the treatment of cluster headaches, trigeminal neuralgia of the maxillary division, and migraine headaches. There is sparse evidence in the literature for the use of SPG blockage in the treatment of neoplasm-related head, neck, and facial pain.1, 2, 3 (Figure 2)


The management of head, neck, and facial pain continues to be an area of needed improvement in the treatment of oncologic patients. The sphenopalatine ganglion (SPG) blockade presented in this case report should be considered as a potential addition to the treatment modalities in this patient population.


  1. Pena I, Knoepfler ML, Irwin A, Zhu X, Kohan LR. Sphenopalatine Ganglion Blocks in the Management of Head and Neck Cancer-Related Pain: A Case Series. A A Pract. 2019 Dec 15;13(12):450-453. doi: 10.1213/XAA.0000000000001106. PMID: 31609721.
  2. Sanghavi PR, Shah BC, Joshi GM. Home-based Application of Sphenopalatine Ganglion Block for Head and Neck Cancer Pain Management. Indian J Palliat Care. 2017 JulSep;23(3):282-286. DOI: 10.4103/IJPC.IJPC_39_17. PMID: 28827931; PMCID: PMC5545953.
  3. Mirabile A, Airoldi M, Ripamonti C, Bolner A, Murphy B, Russi E, Numico G, Licitra L, Bossi P. Pain management in head and neck cancer patients undergoing chemoradiotherapy: Clinical practical recommendations. Crit Rev Oncol Hematol. 2016 Mar;99:100-6. DOI: 10.1016/j.critrevonc.2015.11.010. Epub 2015 Dec 3. PMID: 26712589.
  4. Candido KD, Massey ST, Sauer R, Darabad RR, Knezevic NN. A novel revision to the classical transnasal topical sphenopalatine ganglion block for the treatment of headache and facial pain. Pain Physician. 2013 Nov-Dec;16(6):E769-78. PMID: 24284858.
  5. Forrest, A., Cantos, A., & Butani, D. (2018). How we do it: Sphenopalatine ganglion blockade for migraine treatment. American Journal of Interventional Radiology, 2, 14.


Figure 1: Magnetic resonance image of the cervical spine in sagittal view showing a T2 hyperintense expansile mass extending from the posterior caudal medulla to the C2-3 region (arrow).

Figure 2: Transnasal approach for the sphenopalatine ganglion blockade.

Lumbar Epidural Hematoma after Neuraxial Pain Procedure in a Patient with Chronic Low Back Pain from Spondylosis and Myelomatous Lesions

Wilkinson, AJ; Osborne, AT; Kovitz, CA., Chai, T; Huh BK


The performance of any neuraxial procedure carries an inherent risk of neurologic damage. Bleeding is of great concern in these procedures, as occult spinal epidural hematoma formation in these procedures carries the risk of causing significant neurologic deficits. While the development of spinal epidural hematomas in neuraxial interventions is estimated to be extremely low, the anatomy, medications, and other factors need to be carefully considered along with close adherence to established guidelines for patient safety are necessary to minimize the risk in every patient. We present an 84-year-old woman on secondary anticoagulation with aspirin who underwent a low-risk neuraxial procedure that presented one week later with significant neurologic impairment and pain due to a spinal epidural hematoma requiring emergency decompressive surgery for hematoma evacuation. 


Epidural hematoma after neuraxial pain interventions is rare, the earliest estimate of this complication suggested an incidence of 1:200,000 after a spinal block and 1:150,000 after an epidural block for all patients.1 While risk factors, including the presence of anticoagulants, multiple punctures needed during the procedure, and anatomical variations in vertebral processes, have been demonstrated, case reports have described the formation of spinal epidural hematoma after neuraxial procedures without these traditional risk factors.2 Yet, the complicated care of patients with oncologic processes that induce potential coagulopathy raises the need for further consideration of this complication when considering performing neuraxial procedures. We present the case of an 84-year-old female with an oncologic history of multiple myeloma who presented to the hospital one week after a lumbar spine pain procedure, found to have an epidural hematoma causing severe spinal stenosis necessitating emergency lumbar laminectomy for hematoma evacuation. 

Case Report

An 84-year-old female with a past medical history of multiple myeloma, on maintenance therapy, and a history of lumbar spondylosis, was admitted for severe low back pain and difficulty walking. At that time, she was noted to be on 81 mg of aspirin daily. On admission, she underwent a lumbar “nerve ablation” procedure by a local pain doctor the week prior.

Lumbar imaging by Magnetic Resonance Imaging (MRI) for workup demonstrated a dorsal epidural hematoma at L2, resulting in several central spinal canal stenosis. In the T1 sequence, there was an intrinsic hyperintensity estimated to be 10 mm in the AP dimension and 6 cm in the cranial-caudal dimension which contributed to the several spinal canal stenosis at L2 with constriction of the caudal equina. No cord signal abnormality was detected. Post-contrast imaging demonstrated minimal peripheral enhancement of the dorsal epidural collection. (Figures 1 and 2)

The patient then underwent an emergency evacuation of the epidural hematoma via L2-L4 laminectomy by the Neurosurgery service, without any complications. Postoperatively, she reported significant improvement in her pain and regained the ability to walk at baseline with her walker. 


Any neuraxial procedure carries with it risks, which include vasovagal syncope, post-dural puncture headaches, infections, and bleeding (hematoma formation),4 among others. The incidence of any general neuraxial blockade (GNB) complication is estimated to be between 1/1000 and 1/1,000,000.5 These risks should be considered in every patient, especially in patients carrying the additional risk factors aforementioned in this report. 

Spinal epidural hematoma (SEH) resulting from neuraxial procedures is a rare complication seen in pain management. The estimated prevalence of SEH is 1:200,000 after a spinal block and 1:150,000 after an epidural block for all patients.1 Notably, this estimation does not specify or account for particular risk factors, like coagulopathy, anatomical variations, or technical errors in performing the procedure. Thus, one can infer that a patient without any notable risk factors or any technical errors in performing the procedure would have a smaller risk of complications. This patient stated that she underwent a lumbar “nerve ablation” procedure; therefore, it is unclear what specific procedure was done; however, SEH after nerve ablation procedures appears to have been described in the literature.3

The American Society of Regional Anesthesia’s (ASRA) guidelines for avoiding neurological damage in neuraxial procedures identify the importance of proper imaging and documentation of patient-specific anatomy, avoidance of conditions that lead to increased bleeding, principally concurrent use of anticoagulants or imminent use of anticoagulants, use of proper sterile technique, avoidance of overdosing of local anesthetic during the procedure, and that the procedures be done in a setting capable of necessary resuscitation in the event of serious complications.6 Furthermore, ASRA outlines recommended durations of discontinuation necessary for all classes of anticoagulants and the recommended wait period before restarting of the medication after various neuraxial procedures. These recommendations require physician interpretation of the relative risk of bleeding involved in each procedure, as holding parameters for anticoagulants vary depending on this perceived risk. For this patient, a “high-risk” procedure would require six days of discontinuation of aspirin if for primary anticoagulation, but shared assessment if for secondary anticoagulation or any procedure less than “high-risk.” This further highlights the necessity of this report demonstrating the possibility of spinal epidural hematoma formation even in a lower-risk procedure and patient. All the risks should be considered for each patient, regardless of the level of risk of the procedure, the number of times the procedure has been performed on that patient, or their pharmacologic history. 


Preventing neurologic and hematologic complications in patients undergoing neuraxial procedures remains a top priority within the field of interventional pain management. Even in low-risk patients undergoing low-risk procedures, there is still a chance of potentially devastating complications such as the formation of a spinal epidural hematoma resulting in neurologic injury. This case demonstrates the need for a careful review of each patient’s history, anatomy, and risk factors combined with adherence to published guidelines and close follow-up to minimize the development of bleeding complications after neuraxial procedures.


  1. Chan L, Bailin MT. Spinal epidural hematoma following a central neuraxial blockade and subcutaneous enoxaparin: a case report. J Clin Anesth. 2004 Aug;16(5):382-5. doi:10.1016/j.jclinane.2004.05.001. PMID: 15374561.
  1. Nam KH, Choi CH, Yang MS, Kang DW. Spinal epidural hematoma after pain control procedure. J Korean Neurosurg Soc. 2010 Sep;48(3):281-4. doi:10.3340/jkns.2010.48.3.281. Epub 2010 Sep 30. PMID: 21082060; PMCID: PMC2966734.
  1. Kim SW, Chang MC. Epidural hematoma after caudal epidural pulsed radiofrequency stimulation: A case report. Medicine (Baltimore). 2018 Nov;97(45):e13090. DOI:10.1097/MD.0000000000013090. PMID: 30407313; PMCID: PMC6250492.
  1. Alkhudari AM, Malk CS, Rahman A, Penmetcha T, Torres M. Epidural hematoma after routine epidural steroid injection. Surg Neurol Int. 2016 May 6;7:55. DOI: 10.4103/21527806.181906. PMID: 27213109; PMCID: PMC4866065.
  2. Agarwal A, Kishore K. Complications and controversies of regional anaesthesia: a review. Indian J Anaesth. 2009 Oct;53(5):543-53. PMID: 20640104; PMCID: PMC2900086.
  3. Horlocker TT, Wedel DJ, Benzon H, Brown DL, Enneking FK, Heit JA, Mulroy MF, Rosenquist RW, Rowlingson J, Tryba M, Yuan CS. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus

Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med. 2003 May-Jun;28(3):172-97. DOI: 10.1053/rapm.2003.50046. PMID: 12772135.

Figure Legends:

Figure 1: MRI Lumbar Spine T1 Sequence, Sagittal Section. Annotated arrowheads demonstrating epidural hematoma.

Figure 2: MRI Lumbar Spine T2 Sequence, Sagittal section (left) and Transverse section (right). Arrows showing the location of the epidural hematoma in both views


Evolutionary Medicine: A Focus on Migraine and Psychiatry

Lawrence Robbins, MD

 Evolutionary Medicine is a growing, vital, fascinating and relevant area. I use it daily in my practice, to explain to patients (such as the evolutionary reason for anxiety, why we have so much neck and back pain, why we suffer pain and mortality with childbirth etc…) it should be taught in our medical, nursing, and physician assistant (PA) schools. We could avoid problems by studying evolution.  How best to use antibiotics, and how avoiding blocking certain compounds that are crucial for 400 million years such as CGRP, which certain migraine drugs block, are two examples of how understanding evolution could benefit patients. We ignore evolution “at our peril”.

A Bit O’ History

  • Darwin thought along evolutionary lines: ERASMUS DARWIN, that is… (1790) Erasmus was the grandfather of Charles. Lamarcke (about 1805) built on his ideas. Lamarcke had the right idea (but thought an acquired trait during one’s life could be directly inherited… he believed in “spontaneous generation”)
  • Later in 1858, Charles wrote “On the Origin of Species”. He was hurried along because of Alfred Wallace; they admired each other. Similar to Rosalind Franklin of DNA discovery, Wallace has been unfairly forgotten.

Early objections to evolution (my main thesis as an undergrad) were mainly along religious grounds, and also that early proof was lacking. Although The religious arguments persisted, within 15 years evolution was scientifically accepted.

Why Study Evolution?

  • Goal of medicine is to improve health and prolong life.
  • Evolutionary medicine goals include to:
    • Help develop safer treatments, such as our new CGRP meds to prevent migraine which are possibly dangerous.
    • Change modern behaviors. Historically, we had a healthier diet, and constantly exercised, for 99% of our human existence.
    • Learn to use medications in healthier ways, such as how to manage antibiotics.
    • Help clinicians explain to patients the evolutionary reason for their conditions, such as anxiety, depression.

Proximate vs. Evolutionary

  • Proximate explanation = the nuts and bolts, such as neurochemistry, physiology, etc.
  • Evolutionary = WHY something came about
  • Proximate = a mechanical explanation
  • Evolution = the engineering design
  • Ontogeny = proximate (mechanical, “nuts and bolts”) development of an organism from fertility to egg to adult
  • Phylogeny = evolution and history of a species

Natural Selection

  • Natural selection (NS) depends upon variation.
  • NS operates mainly at the level of the gene.
  • NS involves phenotypic variations driving genotype and phenotype changes over generations.
  • Within a population, variation leads to some individuals being better suited to the environment than others. This results in adaptive changes.
  • Natural selection is going on today; as little as 8,000 years ago, nobody had the genes to digest lactase; now, the genes for lactase are present in over 70% of Northern Europeans. Even by Roman times those genes were becoming more common.

Asking the Right Question

  • The right question (Nesse/Williams): Why are we so vulnerable to various diseases?
  • The wrong question: what evolutionary advantage does each disease have? (yes, they may have advantages, but often they do not).
  • Albert Einstein said, if given 60 minutes to solve a problem, he will take 55 minutes to come up with the right question.
  • Jonas Salk: “Solutions… they come through asking the right question, because the answer pre-exists”…

6 Principles of Evolutionary Medicine

  • Randolph Nesse pioneered much of this thinking: (Nesse and Williams):
    1. MISMATCH: our environment has changed, we are adapted for a radically different (ancient) environment.
    2. TRADE-OFFS: many (most) aspects of human anatomy and physiology involve trade-offs.
    3. EVOLUTION cares about reproduction and propagating one’s genes; it DOES NOT CARE about: health, happiness, longevity (except for possibly the “grandmother hypothesis: nurture and epigenetics”).
    4. PATHOGENS can replicate much faster than humans; hours versus our 18+ years. Pathogens will usually win the evolutionary arms race.
    5. DEFENSES: many symptoms are often defenses, not diseases (fever, nausea/vomiting, cough, diarrhea).
    6. NATURAL SELECTION and evolution are LIMITED; there are constraints on what selection can do; evolution tinkers, it does not invent.

Mismatch with the Environment

  • Ten to twelve thousand years ago we began to cultivate agriculture.
  • We morphed from hunter-gatherers (H-G) — more accurately called “forager-gatherer-fisher-hunters” — to agriculture-based societies.
  • Changes in our environment include:
    • agriculture
    • a move towards dense, urban populations
    • artificial light, less sunlight, & light at night
    • Houses
    • Reading
    • Pollution
    • sterile food/water
    • solo sleeping
    • bottle feeding
    • Antibiotics
    • other medicines
    • sleep changes (less sleep)
    • steady food with less food insecurity and less fasting
    • heating and cooling
    • long-term marriage
    • birth control
    • mass media and social media
    • louder sounds
    • change in diet to high starches (beginning 14,000 years ago): led to many problems
  • Approximately 50% of diseases are strongly influenced by environmental changes (mismatch with our previous environment)

Evolution and Migraine

  • Migraines increased as we moved to more northern latitudes. Low vitamin D levels and the TRPM8 gene play a role. TRPM8 is linked to decreased sensitivity to both cold and migraine.
  • Migraine due to mismatch with our modern environment, including increased light, sound, stress, immune response (possibly tied into ridding ourselves of worms/parasites), lack of exercise, urban density (and an increase in infections), poor sleep, changes in diet, pollution, electronics and social media, etc…
  • Migraine may have occasional evolutionary advantages such as an enhanced immune response could be helpful in fighting certain infections. it is speculated that the rates of mating and fecundity among migraineurs may be increased, and more research is needed. In the past most people died of infections. If one is laid up with a migraine when a virus sweeps through, the migraine may enhance survival.
  • Why migraine is much more common in women is unclear. Migraine often decreases during pregnancy, offering a small evolutionary incentive for more pregnancies.
  • Hunting/fishing were often done more by men; migraine may pose disadvantages for these activities.
  • Women did more of the foraging; migraine may not have as much of an effect on foraging, although this is unclear.
  • Why does migraine only affect humans? It may be that our ancient human brainstem has difficulty coping with a newer cortex that is vastly enlarged. Higher cortical functions may add to our continued vulnerability to migraine.
  • Migraine could be a defense mechanism against excessive stress, noise, or light.
    • Migraineurs have an enhanced sensitivity to smells; this may be protective from toxins or viruses entering the CNS. Vomiting from a migraine may remove toxins.
    • Women with migraine (probably) have a lower incidence of Type 2 diabetes.                                                                                    
    • Activating the trigeminal nuclear complex could be protective to the migraineur.
  • If a migraineur has 100 migraines in a year, and just one protects from harm, the trade-off may be worthwhile. Evolutionarily, the cost of migraine may be inexpensive.
  • Headache and pain are adaptive. Being still in bed may help with repairing damaged tissues.
  • As mentioned, mismatch with our modern environment, with radical changes over 12,000 years, is a primary driver for the increase in migraines.
    • Cultural changes (social media etc.) also may play a role.
    • The elimination (past 140 years) of worms/parasites in our GI systems has led to an increase in autoimmune illnesses. Migraine is probably (somewhat) autoimmune.

Migraine, Evolution, and our CGRP Therapies-

  • CGRP monoclonal antibodies to prevent migraine were introduced 2018. They are effective, but these have many short term adverse effects (in the 1st 3.5 years, 50,000 adverse events reported to the FDA, and 7,000 serious ones).
    • We do not yet know long term effects. CGRP has been in animals for at least 350 million years and is ubiquitous throughout our body. Blocking CGRP for years (or decades) ignores all of it’s numerous evolutionary advantages. If we paid attention to evolution, we may not have pursued the avenue of blocking CGRP.
    • We ignore evolution at our peril!

Further reading and YouTube viewing on Evolutionary Medicine:

There are excellent books, but I recommend searching YouTube: many outstanding talks on evolution and medicine

  • Books: Why We Get Sick by Nesse and Williams, Human Errors by Lents, Good Reasons for Bad Feelings by Nesse, Evolution and Medicine by Perlman
  • Robert Sapolsky is a marvelous author and speaker (many talks on YouTube: he was Scientist of the Year (U.S.) and has a newer book out, “Behave” that incorporates evolution and behavior
  • Principles of Evolutionary Medicine by Gluckman et al., Evolutionary Psychiatry by Brune, The Third Chimpanzee by Diamond, Chaos and Life by Bird, The Evolution of the Human Head by Lieberman, Evolution In Health and Disease by Stearns et al, The Lives of the Brain by Allen, Sapiens by Harari, The Riddled Chain by McKee, Evolutionary Medicine and Health by Trevathan et al.


  • An excellent lecture is “An Evolutionary Model of Depression” by Markus Rantala
  • YouTube: There are hundreds of excellent lectures and discussions.
    • Randolph Nesse has a plethora of videos and interviews; Yale Medicine and Steven Stearns has a series of excellent videos; Nathan Lentz is outstanding; Robert Sapolsky as mentioned above, and many others.

Evolutionary Psychiatry (EP)

  • Anxiety and the “Smoke Detector Principle”
    • At the watering hole on the Savannah, if the chance of getting eaten is even 1 out of a thousand, it is worthwhile to run away every time; this is “adaptive”
    • However, if we start having panic attacks for no reason, this is “maladaptive”… the margins between adaptive and maladaptive can be blurry… and it all depends on the context in which the behavior occurs.
  • The stress response is a product of millions of years of selection. The system is usually adjusted and turned off due to its costs. These adjustments include a minimized immune response during stress along with an increased metabolism.
  • Even in fish, timid fish survive predation more than bold ones…
  • Even now, evolution is occurring: red squirrels around Chicago are disappearing, as they are bolder than the grey squirrels, and don’t run away from cars. The timid grey squirrels are surviving
  • Many behaviors are observed in humans and primates, and all the way back to fish or even fruit flies! Many animal behaviors do not change from genus to genus.
    • When emotions become maladaptive, they become a “psychiatric illness”
    • Anxiety costs energy, due to catecholamine release and cortisol depletion. Energy (or the lack of) and ATP governs much of animal behaviors and evolution.
    • Chronic stress and anxiety become maladaptive, with deleterious effects.
    • Phobias can be viewed as maladaptive forms of what would be healthy adaptive thoughts in a different environment. Phobias arise out of a perceived danger from attack, trauma, or predation. What might be a reasonable response in a context 2 million years ago is unreasonable now. We are unlikely to have problems from snakes, spiders or sharks, but these phobias persist…
  • Adolescent behavior of pushing, attention seeking, impulsivity, and aggressiveness can be an advantage for mating and reproduction. Remember, evolution cares not for how happy you are, or how long you live. Evolution cares most about propagating genes.
  • Risk taking can also help in food acquisition.
    • Male risk taking (peaks in adolescence) succeeds evolutionarily. It leads to more reproduction, but also contributes to many earlier deaths.
    • At age 20 (and most other ages), for every 100 women who die, on average 350 men die, partly due to risky behaviors. This number varies between countries. These risky behaviors lead to more procreation (which is the purpose of evolution), but also leads to death. Men are also more vulnerable to certain diseases. Men are 2 to 3 times more likely to die of cancer or heart disease. An increase in procreating, but dying earlier, is a classic trade-off.
  • ADHD could possibly have adaptive survival benefits. In the forest, it could conceivably be beneficial to be unfocused and constantly looking around. However, it is more likely that ADHD is not very beneficial, but rather it is one of many illnesses that evolution simply cannot delete out of our genome. Schizophrenia is another such illness. One percent of people are schizophrenic in almost every country. Schizophrenia results in no evolutionary advantage for survival.
  • Certain personality disorder (PD) traits (aggressiveness, salesmanship, paranoia, alpha behaviors, and the “charming- seductive” behaviors) can result in increased mating and reproduction. This is part of the reason why PDs persist. The other reason that these genes persist is the plethora of different genes involved in PD pathology. Evolution has no easy way to delete these genes.
  • DEPRESSION: The different symptoms can be adaptive — if fighting an alpha male, submissive and depressed behavior may enable immediate survival. Low mood may allow an organism to recover from an infection more easily by not moving about. Depressed people may show little movements of the eye and mouth region, avoid eye contact, speak softly, and remain socially inactive. These all have advantages in certain contexts.
  • In a situation where appeasement is necessary, and inferiority or defeat is present: the non-verbal behaviors of depression may lower aggression by others. Catatonia may be an extreme example of ancient defense mechanisms.
  • Dominance, submission, and social hierarchy are inherent in most primates (and other animals, going back 400 million years). The winner and loser in a clash ideally both remain within the group. In ancestral environments, exclusion would have meant death.
  • Human life is dependent on a complex web of interactions with other humans, more than in other primate species.
  • Why do women have more depression than men? Outside of the proximate “nuts and bolts” explanations, evolutionary sex differences play a role. Women (more than men) depend upon social support. Women have had less ability (for several reasons) to leave a bad relationship/marital situation, with depression as a consequence. This may go back to ancestral times.
  • Many theories as to why we become depressed have been put forward.
    • Early work focused on infant attachment.
    • Negative life events may trigger low mood or depression, and also loss of social status. Hunter-gatherer societies experience the low mood but not nearly as much of the depression. Depression is rampant in Western societies.
    • These theories are outlined in the excellent book by Randolph Nesse, MD: Good Reasons for Bad Feelings (2019)
  • Depression is much more prevalent in Western societies
    • Depression (and anxiety) has increased from 2008 to the present; probably mismatch with the environment (social media, smartphones, pollution, etc.) and world stresses (pandemics, politics, war)
  • As mentioned, little depression is observed among various hunter-gatherer societies, and also among the Amish.

 EP — Depression, Inflammation and evolution

  • Inflammation plays a role in depression; our “modern’ diet plays some role in this…
  • Western society has more inflammation than hunter-gatherer societies
  • Our lifestyle and subsequent mismatch with the modern environment are factors
  • GI worms/parasites downregulate our neuroimmune response; since ridding ourselves of these in the past 120 years, inflammation has skyrocketed!
  • A “depression symptomatic” approach fits into evolutionary thought: the idea is that depression is a description of a number of different symptoms but not a “disease” itself. There is some evidence that simply asking about “low mood” is just as accurate for diagnosing depression as using DSM-5 criteria. A MDD diagnosis is not that helpful in guiding specific treatments.
    • The “depressive symptomatic” approach evaluates the varying symptoms, each of which can be treated. The symptoms influence each other in a feedback loop: for instance, insomnia causes fatigue, which increases low mood, which then exacerbates insomnia.
    • If we perturb one part of this system, the system will read just itself into a new homeostasis: if we decrease the insomnia, the fatigue is lessened, and then the depression may be better.
  • Each particular symptom could be adaptive in an evolutionary sense; the symptom becomes maladaptive if it is pathologic and causes undue distress, such as panic attacks. Adaptive vs. maladaptive varies depending upon the environment and context in which it occurs.
  • Sadness/emotional pain could be adaptive in that they lead to avoidance of actions that may result in more losses.
  • Crying elicits empathy and support from other group members. Exclusion, real or threatened, from a group may lead to depression. Loss of social status or hierarchy triggers depression.
  • Fatigue helps conserve energy and may be adaptive.
  • Seasonal affective disorder (SAD) may help to conserve energy in winter. In winter if a primate hunkers down, possibly due to low mood, and does not go out in the cold, energy is conserved.

EP and Mania

  • Mania may represent the pathologic extreme of dominance behaviors. Dominance and risky behaviors may lead to increased mating and reproduction (the goal of evolution).
    • Mania could also be a compensatory mechanism to view the world as less threatening.
  • Hypomania/hypersexuality = may result in increased mating.
  • Mixed states: one theory — mania is generated more from the cognitive/cortex level, and appeasement/depressive behaviors from the reptilian (older) brain.
  • In dysphoric mania, evolutionarily the mania could offset that pervasive hypervigilant fear that is so often present.

EP, cont…

  • Selection favors traits that promote fitness in our social environment such as: cooperation, reciprocal altruism, the ability to interpret actions of others, and also to detect freeloaders within the clan.
  • Altruistic behavior lowers group stress, increasing survival of all group members.
    • What may look altruistic may actually be survival of the individual (the famous Wild Kingdom Wildebeest episode)
  • An increase in cortical neurons, and acquisition of language, resulted in more complex group behaviors.
  • Human behavior also involves mating choice, kin selection, social group living, etc. For more on human behavior, check out Robert Sapolsky’s books (particularly his book “Behave”) and YouTube talks.
  • Schizophrenia and bipolar share many genes, spread throughout the genome. Autism and schizophrenia also share similar genes.
  • The multitude of genes, spread throughout, is one reason evolution cannot easily delete “bad” genes. Mutations also play a role in creating “new” psychiatric illness. When many genes are involved it renders it impossible to cure these illnesses through any type of “gene therapy”.
    • There are exceptions, where a cure is conceivable, such as Huntington’s (a specific CAG repeat)
  • For men, appeasement and submission do NOT pay off with increased mating. However, they may enhance survival. The differences in male vs. female depression may go back millions of years.
  • For men, social status = crucial towards mating and reproduction. Higher social status = more mating.
  • Lack of social support from elderly kin leads to increased risk for depression.
  • We are clannish by nature: “The oddity effect”: animals don’t associate or align with phenotypically different individuals. This goes back to fish, birds, mammals and even plankton! Clannish nature may contribute to “otherism”, and possibly racism as well.
  • This may be the origination of human bullying (“appearance-based bullying”), and helps to explain xenophobia.
  • Within a group, those that look the most like the group tend to be the worst bulliers.

 Vasovagal syncope is probably adaptive. It is paradoxical: fainting in the face of perceived danger. The syncope could be adaptive in certain dangerous situations, so as to survive as a younger adolescent. In primates, when fighting a stronger alpha male, it is adaptive to faint and then have a chance at survival.

  • Vasovagal syncope is observed in adolescents of other primate species.
  • Humans are sensitive to early stress or trauma. As with most behaviors, this is true for other species as well. Even fish are sensitive to early stresses! In primates the effects of stress begins in utero (if mom is stressed, cortisol changes result and this greatly affects the fetus). The vital amygdala-prefrontal cortex connectome is greatly influenced in utero and in the first year of life.
  • Aggressive and alpha behavior can be learned (as demonstrated by fish: the fish that lost the battle with an alpha fish, then was allowed to watch the alpha fish interact with others, subsequently learns to act like an alpha fish).
  • Taking an ethological (observing behavior in various species) approach, depression may be observed in most species.
  • These species include primates, voles, rats, and (There is an excellent YouTube talk on this: An Evolutionary Model of Depression, by Markus Rantala)
  • The pelvis changes that resulted from going bipedal contribute to our difficulty with childbirth. Human mothers have more childbirth pain than other species. Human infant and/or mother mortality has been 10 to 20%. The baby has to rotate and flip. Our large skull size also contributes to the childbirth difficulties. We are born relatively immature, as compared to other primates, partly due to our large head: we are born earlier than is ideal.

President’s Message: A Fresh Approach to Pain Education

Harry J. Gould, III MD, PhD

During the past 30 years, we have observed the prescribing habits of physicians swing from a position of avoidance of opioid medications in the late 80’s and early 90’s to a position of liberal and virtually indiscriminate prescribing of opioids in the first decade of this century.  This trend paralleled a similar rise in overdose deaths associated with prescription opioids that led to the development of Washington State’s Multiagency Guidelines for Prescribing Controlled Substances with the goal to improve the safety and effectiveness of opioid treatment for chronic non-cancer pain.  Concern about the over prescribing and overdose deaths motivated the Institute of Medicine’s investigation of pain in America, the Centers for Disease Control’s declaration that the “Opioid Epidemic”, was considered the greatest healthcare crisis in U.S. history and the release in 2016 of their Guideline for Prescribing Opioids for Chronic Pain.

The broad understanding and agreement that the problem exists coupled with a desire for a rapid solution led to varied interpretations of prescribing guidelines.  Imposed policies and benchmarks for treatment standards often exceeded the intended goals of the drafters of the guidelines.  Physicians’ fear of criminal sanctions and strict disciplinary consequences associated with failure to comply with guideline standards led to a dramatic decline in prescriptions issued for opioid medications.  Unfortunately, the rapid reversal of the pendulum related to opioid medications, while significantly reducing the availability of prescription opioid medications has not produced a parallel reduction in opioid-related overdose deaths and the pendulum representing improvement in patient care seems to have remained steady throughout this period of healthcare volatility. How can we move closer to our goal of providing appropriate and adequate care for our patients in pain and mitigate the problem of the untoward adverse effects of opioid medications on patients and on society as a whole? 

“Across health care and society alike, there are major gaps in knowledge about pain” was one of the important conclusions drawn from the Institute of Medicine’s investigation of the state of pain care in America.  This is an important focus, but moving the mark toward improved patient care takes time and a concerted effort from a vast number of healthcare providers who view the problem from varied perspectives and training, from administrators and regulators of practice standards and from the patients we are hoping to serve. Incumbent on the approach to developing strong, patient focused principles for pain management is understanding that there are many tools that are effective for treating pain, but not all tools are necessarily appropriate or effective for treating every pain problem.  Each patient should be properly evaluated and should be involved in setting reasonable goals and making decisions in their care.  The appropriate tool or tools for the problem and the rationale for implementation should be carefully selected and administered when optimum.      

To this point, a new program to address the problem of provider and patient education has begun a trial run at the Louisiana State University Health Sciences Center in New Orleans.  The program is a longitudinal study targeting physicians in training in various specialties.  The program is administered to residents-in-training across the entire spectrum of their training and focuses on pain as it applies to their specialty. It measures levels of understanding of pain, its evaluation and management at each level of training and as they progress through their program toward certification. The initial trial runs focused on residents in obstetrics and gynecology and in orthopedics.  As a point of reference, patient assessment and education is approached at stages of evaluation and planning, pre-operative instruction, intraoperative and post-operative care and discharge planning for procedures that are frequently performed or are particularly problematic within their area of specialty.  Issues related to pain, its management and patient education are discussed and reviewed in the laboratory including gross dissection and classroom with attending faculty with expertise in the basic science of anatomy, pharmacology and physiology and in the clinical sciences with specialty training in pain medicine, anesthesiology, physiatry, psychiatry and the appropriate surgical specialty.  Basic knowledge is assessed before and after each training session and will similarly be evaluated throughout residency training.  It is hoped that the participants in the program will gain a better understanding of how to better evaluate pain, how and why certain management tools are selected, when they should be applied and how to help their patients understand and participate in their own care. 

The cohort of trainees was selected because residents in training are at the steepest part of their educational growth curve where information provided and reinforcement of the basics is likely to have the greatest effect.  It is also appreciated that residents play a major role in mentoring and laying down the foundations of practice for medical students at the earliest stage in medical training and a level where the emphasis on training compared to the prevalence and influence on pain healthcare is very low. In this teaching role, the residents are likely to have challenges to newly learned principles and be able to reinforce what they have learned. Finally, residents are in a position to challenge and inform attending physicians of recent advances in arts complimentary to their specialty.  I am encouraged, thus far, with the progress that this program has made and look forward to the possibility that it may impact some of the negative perceptions that we inherit when embarking on a career in pain medicine.

President’s Message: When Was That Taught?

Harry J. Gould, III MD, PhD

It has been more years than I care to admit since I graduated from medical school. As most of us have realized, with time, advances are made, with experience, skills are refined and as practitioners, we adapt to change and challenge and improve in our ability to care for patients. An unfortunate corollary to the essential fine-tuning of the evolving practitioner, especially in specialty and sub-specialty practices, is that many components of our general training are infrequently called to bear in daily practice, are less well remembered, and suffer from lack of reinforcement. I have recently been more aware of this disappointing realization both in my own practice when confronted with patients suffering with problems involving infectious disease, endocrinology, hematology, pulmonology, cardiology, and gynecology and from a different perspective, in observing the practices of colleagues who consult me for recommendations to help care for their patients in pain.  Some problems require complex solutions, but surprisingly, most can be addressed simply by returning to the basic principles learned in those early courses when we received so much “irrelevant material”.

My reason for addressing this topic is that I have noticed, more recently, probably over the last 2-3 years, that well over half of the consults directed to our in-patient consultation service for pain management have inquired as to what else can we recommend to control pain and/or whether an additional opioid medication should be added to the analgesic regimen to improve pain control for a patient. Virtually all of the presenting analgesic regimens in these cases, regardless the type of pain or pain history, include gabapentin < 300 mg daily, a muscle relaxant, and not atypically, orders for multiple formulations of mu-opioid analgesics, e.g., hydrocodone PO as needed for pain between 3-6/10 in intensity, oxycodone PO as needed for pain > 7/10 and hydromorphone IV scheduled every 3-4 hours.  The total daily morphine milligram equivalents (MME) ordered is, not infrequently, less than that in the patient’s routine outpatient regimen for chronic pain. It is possible that the initial ineffective treatment regimens have been designed in an attempt to comply with published guidelines designed to minimize opioid use, but it seems more likely that the failed attempts reflect a prevailing assumption that complex problems require complex solutions.  Obvious to a specialist, but not so to the physician with medical school a distant image in the rearview mirror of life, is that simple solutions within recommended guidelines are more often likely to produce favorable outcomes because they are less likely to introduce complications that lead to confounding results.

More efficient use of the dynamic interaction between referring physician and consultant may be the best way improve patient care because the best learning opportunities seem to occur when therapeutic approaches are introduced or reviewed in the context of administering in real-time to an interesting patient or a problem situation (“When I was a resident, I had a patient that…”) and take less time out of a busy practitioner’s day than a formal course for review.  A referral for consultation provides a platform for the specialist to offer a focused review of basics from their specialty that reinforce optimum therapeutic approaches for managing a given problem and a platform for the referring team to provide feedback to the specialist as to the rationale for either accepting or declining to implement a given recommendation.

In the offered example, a good place to start might be to determine and establish an analgesic treatment base before embarking on diagnostic tests or therapeutic treatments that are likely to produce additional pain. The process of determination would be comprised of an assessment of the type of pain that is being experienced, a determination of co-morbid problems and whether the patient has had or is currently receiving medications, especially opioids, for a previous acute or a chronic problem, for which medications had been used and if current, what dose is being taken. It also would seem reasonable to take advantage of prior history and to start with a medication that has been shown to be effective for the particular patient and to anticipate that any new pain may require MME dosing equal or greater than the premorbid regimen to achieve adequate pain control and to prevent the onset of withdrawal symptoms. The pharmacologic principles that simple, monotherapy regimens are easier to administer, have higher rates of compliance and are more effective are generally good principles to follow when designing a treatment regimen.  Mu-opioid agonists due to chemical configuration and available routes of administration have different benefit potential and different side effect profiles that provide the basis of therapeutic selection.  Unfortunately, analgesic benefits of mu-agonists are achieved through a single mechanism of action, regardless the formulation precluding a hoped for reduction of daily MME by providing treatment with multiple mu-opioid agonist at low doses. Furthermore, the simultaneous initiation of treatment with multiple formulations complicates the recognition of which agent(s) might be responsible for any benefits or adverse effects observed.  Because of incomplete cross-tolerance between mu-opioid agonists, the concurrent use of multiple formulations, also effectively eliminates or greatly reduces any possibility for drug rotation, if needed. Thus, selecting a single mu-agonist formulation, determining the route of administration and the proper dosing allows for early identification of tolerance and dosing efficacy. Finally, the use and selection of potentially beneficial adjuvant agents based on pain type and benefits that may be realized from their otherwise adverse, side effect profile, e.g., drowsiness in patients with difficulties sleeping, are important components of the analgesic regimen that are likely to produce benefit without undesired adverse effects if they are prescribed in adequate doses. 

In the midst of the exponential growth in technology and continued advances in the era of information explosion that often lead to overwhelming increases in system complexity, it may be comforting to remember that the old, simple, basic principles that we learned as fledgling healthcare providers are still useful and may be our best means for caring for our modern day patients in a rapidly expanding and changing world of pain medicine.

Treatment of Refractory Chronic Migraine With Worm Eggs: A Therapy Rooted in Evolution

Lawrence Robbins, MD and Hanah Alley, MD

(originally published in Medicine Connections, 2021 vol.1, issue 2: a journal of the World Headache Society)


Introduction: This was a small open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine (RCM) patients. It is probable that the immune system is involved in migraine.1 Helminth worms have populated the GI tract of primates for millions of years. They downregulate the immune response. When the helminths (and other parasites) are removed, the result may be an increase in autoimmune illness. The immune system and inflammation are involved in migraine pathophysiology.

Study design:  Eleven RCM patients were enrolled. After the run-in period, patients ingested the helminth eggs every 2 weeks for 5 months.  These eggs were from the pig whipworm, T. suris. The primary endpoint involved the number of moderate or severe headache days per month. The first (run-in) month was compared to the last 2 months of active therapy. Secondary endpoints included disability, depression, anxiety, and quality of life.

Results:  5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 of the 5 patients who met the primary endpoint.

4 of 11 patients who completed the study did not meet the primary endpoint. 1 other patient did not supply data, and another discontinued treatment due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not improve.

Conclusion:  This study indicates that there may possibly be a role for helminth therapy in treating refractory chronic migraineurs. 5 of 11 patients did well. This treatment is rooted in evolution. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may possibly help in the treatment of conditions that involve the immune system, such as migraine.

Keywords:  Migraine, Refractory Migraine, Headache, Helminth,  Evolution, Chronic Migraine, long haul Covid worm eggs,


The concept of migraine as an autoimmune entity has been discussed for many years.1 Migraine is a common disabling neurological disorder. Despite available therapies, a subset of patients remains unresponsive to preventive treatment. Individuals with Refractory Chronic Migraine (RCM) have failed a number of the available preventatives, and suffer from frequent moderate or severe headaches2,5. Individuals with Chronic Migraine (CM) are those with a headache occurring on 15 or more days/month for more than 3 months.  For at least 8 days/month their headaches are migrainous.4,6  The pathophysiology of migraine is interwoven with the immune system, which is the reason for the current study7,8.

Helminth worms have co-existed in primates for millions of years. Helminths, along with other parasites, downregulate the human immune response. In many human populations, the helminths have largely been eradicated. This resulted in an increase in autoimmune illness. 9,10,11,12,16,17,18.

There is a robust literature, dating back more than 20 years, introducing helminth eggs into the GI tract of those with various autoimmune illnesses. 

Helminth therapy has been extensively evaluated for its safety and efficacy in the context of autoimmune diseases9,10,11,15. These include Inflammatory Bowel Disease (IBD)9,10,12, Type 1 Diabetes Mellitus (T1DM) 16,17 and Systemic Lupus Erythematosus (SLE)12,13,18. Helminths elicit an immune response by promoting production of anti-inflammatory mediators14,15,19,.  The result is to downregulate the host immune response to various antigens9 .

Helminths have lived in the GI tract of primates for millions of years.  Over time, a homeostasis was achieved between the parasites and the host immune system.  The host primate’s immune system has been downregulated in response to the helminths. It is easy and relatively safe to reintroduce helminth eggs into the GI tract.  This study was undertaken in order to assess the effect of introducing helminth eggs into the GI system of patients with refractory chronic migraine.


Study patients:  Eleven patients (10 women, 1 man) with the diagnosis of refractory chronic migraine were enrolled in the study. Refractory chronic migraine was defined according to the European federation consensus.2 They were patients well known to the treating physician.  Ages ranged from 25 to 67. Patients’ names and information were de-identified.

Study Design: This was an open label study designed to determine efficacy of helminth egg therapy in refractory chronic migraine patients. The study included a one-month run-in prior to the actual treatment phase.  Patients then were to receive the helminth eggs every 2 weeks for 5 months.  There were 11 total doses of the eggs.  Patients kept daily track of the headache severity. They used a simple paper calendar.  A visual analog scale, 1 to 10, was utilized. A headache day was considered moderate to severe if the severity was rated 5 or greater. Mild days were listed but did not count for the purpose of this study. IRB approval was obtained. The IRB was through Advarra: PRO ID# 00051859, CR 00316902.  Possible risks were explained, and written consent was obtained.

The patients were allowed to remain on stable preventive medication/approaches. They were asked not to add new preventive medication or approaches. To our knowledge, none of the patient received new preventive medication during the study.

Safety of the Eggs: The eggs are from the whipworm, Trichuris suis. Safety of these eggs has been evaluated for 20+ years. There have been various studies, primarily regarding autoimmune illnesses.  Patients have also been able to order the eggs from the Tanawisa Company. Over 36,000 patients have ingested the eggs. There is a helminth therapy Facebook group.  The eggs have not produced adverse effects, except for occasional mild diarrhea14. There was one instance of eggs maturing into actual worms (which are benign). The company stated that it was unclear whether the eggs actually contributed to that one case.  We had multiple conversations with the Tanawisa Company regarding safety. The eggs are contained in a solution with 98% viable eggs. These attach to the mucosa surrounding the caecum. The eggs release molecules that induce regulatory T-cells by the human host. In theory, with a severely compromised GI mucosa, the eggs could attach and hatch, although this has not happened in the studies involving GI illness. We did not allow patients with GI mucosal illnesses to participate. The eggs “modulate” the immune system, but have not resulted in infections or immune deficiency issues. The eggs were donated by Tanawisa, the company that produces them. The company has extensive safety and efficacy information on  The results of the studies, and extensive information on safety and risks, were given to all patients as part of the informed consent.  A number of these studies are listed in the reference section below. There has been no evidence that the egg exposure actually compromises the immune system, or leads to infection or immune based problems.

Patient visits and lab tests:  Patients were seen in person prior to the run-in month, after 1 month, after the 3rd month, and after the 6th month. Patients were given the egg solutions to ingest every 2 weeks, and the solutions were stored in their refrigerators. In addition, phone visits were done after the 2nd, 4th, and 5th months. A physical exam was performed on the first visit, at the 3rd visit, and after the final visit. An ECG was performed prior to the study. Blood tests (cbc, cmp, TSH, T4, sedimentation rate, ANA, and Hemoglobin A1c) were drawn 2 times: prior to month 1, and after month 3. All visits and blood tests were at no cost to the patient.  

Screening tests: These were done prior to the study, and after the last visit. The screens included the Beck Depression Inventory, the Beck Anxiety Inventory, Migraine Disability Assessment Test (MIDAS), and the Health Related Quality of Life Measure (number of unhealthy days per month).

Beck Depression Inventory:  1 to 10=none, 11 to 16=mild mood disturbance, 17 to 20= borderline clinical depression, 21-30=moderate depression, 31 to 40= severe depression, 40 or more=extreme depression.

Beck Anxiety Inventory:  0 to 7=none or minimal, 8 to 15=mild, 16 to 25= moderate, 26 to 63=severe.

MIDAS:  0 to 5=little or no disability, 6 to 10= mild, 11 to 20=moderate, 21 or more=severe.

HRQOL:  # of unhealthy days per month: maximum number= 30 days per month

Refractory Chronic Migraine Severity Scale: This scale was developed by Lawrence Robbins, and separates patients into mild, moderate, and refractory chronic migraine. Ten criteria are used in the scale. (5)

Inclusion Criteria: Patients known to the Robbins Headache Clinic, 18 to 70 years old.  Each patient had a well-established diagnosis of chronic migraine, according to ICHD-3 criteria (4). Every patient had the diagnosis of refractory chronic migraine (RCM)(2). The patients were graded as to the severity of the RCM (5).

Exclusion Criteria:  1. Patients with IBS-D or other gastrointestinal conditions that would result in diarrhea. Patients with a compromised GI mucosa due to a GI illness were excluded, 2. Severe psychiatric or medical illness which, in the judgment of the PI, might endanger the patient, 3. Use of probiotics during the course of the trial, 4. Inability to adequately track the headaches and side effects, Any other condition that would interfere with the ability of the patient to successfully complete the study, and 6. Pregnancy: See pregnancy section below.

Medication Use: Patients were allowed to continue on their usual medications. If possible, patients were encouraged not to change the dosage of their preventive medications. They were also asked not to start new preventive medications. If necessary, medications changes were allowed. If patients needed to take an antibiotic that opposed the action of the egg solution, they would be discontinued from the study.

No patients changed preventives during the trial. The doses of their pre-existing preventives were kept steady throughout the trial.

Pregnancy:  There is not enough evidence to state that the eggs are safe for use during pregnancy. If pregnancy was being considered, the patient was excluded from entering the study. For those women where pregnancy was not being considered, but was possible, adequate birth control methods were to be employed. To our knowledge no patient became pregnant during the trial.

Safety Monitoring and Adverse Events/Adverse Effects:  Dr. Robbins or the study coordinator conducted monthly discussions with each patient about adverse events and adverse effects.  Patients were encouraged to report any new effects, particularly GI adverse effects.

Primary endpoint: The number of moderate or severe headache days during months 5 and 6 (average of the 2 months), as compared to the number of moderate or severe headache days during the run-in period (first 30days).   Success is a decrease in monthly moderate or severe headache days by 3 or more days per month. Moderate or severe was a 5 or greater on the 1 to 10 severity scale.   

Secondary endpoints: 1. Disability assessment before and after the study (MIDAS), 2. Evaluation of depression before and after the study (Beck Depression Inventory),  3. Comparison of anxiety after the study versus during the run-in phase (Beck Anxiety Inventory) and 4. Evaluation of a quality of life assessment before and after the study (Health-Related Quality of Life Scale, as measured by the number of unhealthy days per month).


Patient #1: 42 y.o. F with moderate refractory chronic migraine (RCM).

Pre-study month (run-in) # of moderate or severe headache days: 30

Month #1 (active study): 30 moderate to severe days

Month #2: 24 days

Month #3: 24 days

Month #4: 22 days

Month #5: 22 days

Midas (disability): pre-study=51, post-study=30

Beck Depression: pre-study=0, post-study=1

Beck Anxiety: pre-study=6, post-study=3

QOL: pre-study # of unhealthy days per month=30, post-study (the last month)=26

Summary: The # of moderate or severe headache days did decrease from 30 to 22 (average of the last 2 months). Disability remained high but improved. Depression was low (pre and post) and anxiety, which was mild pre-study, did lessen.

Patient #2: 39 y.o. F with mild RCM.

Pre-study month (run-in): 20 moderate or severe headache days(and 6 mild days)

1st  (active) month: moderate to severe days: 13

2nd month: 15

3rd month: 12

4th month: 8

5th month: 6

Midas: pre-study= 18, post-study=9

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=5, post-study=3

QOL: pre-study= 0, unhealthy days, post-study= 0

Summary: The # of moderate or severe headache days decreased from 20 pre-study to 7 (average of the last 2 months). Midas disability improved. Depression was low and anxiety, which was low, did improve.

Patient #3  36 y.o. F with moderate RCM.

Pre-study month (run-in): 9 moderate to severe headache days(and 11 mild days)

1st month (active): 7 moderate to severe days

2nd month: 3

3rd month: 2

4th month: 2

5th month: 2

Midas: pre-study=15, post-study=8

Beck Depression: pre-study=0, post-study=0

Beck Anxiety: pre-study=3, post-study=0

QOL: pre-study=7 unhealthy days, post-study= 0

Summary: The # of moderate to severe headache days decreased from 9 pre-study to 2 (average of the last 2 months).  Midas disability improved. There was no depression, and anxiety, which was low, did improve. The # of unhealthy days dropped significantly.

Patient #4   68 y.o. F with moderate RCM.

Pre-study month (run-in): 15 moderate to severe headache days(and 7 mild days)

1st month (active): 11 moderate to severe days

2nd month: 5

3rd month: 5

4th month: 5

5th month: 2

Midas: pre-study=42, post-study=30

Beck depression: pre-study=7, post-study=8

Beck anxiety: pre-study=12, post-study=8

QOL: pre-study=4 unhealthy days, post-study=4

Summary: The # of moderate to severe headache days decreased from 15 pre-study to 3.5 (average of the last 2 months).  Midas disability improved. Depression did not change, and anxiety improved.  The # of unhealthy days remained the same.

Patient #5 65 y.o F with severe RCM.

Pre-study (run-in): 8 moderate to severe headache days(and 12 mild days)

1st month (active): 9 moderate to severe days

2nd month: 4

3rd month: 5

4th month: 5

5th month: not recorded

Midas: pre-study= 131, post=100

Beck depression: pre-study=4, post=6

Beck anxiety: pre-study=23, post=5

QOL: pre-study=30 unhealthy days, post=30

Summary: The # of moderate to severe headache days decreased from 8 pre-study to 5 (4th month). Midas disability improved. Depression was slightly worse from pre-study to month 4. Anxiety improved significantly. The # of unhealthy days remained the same.

Patient #6  55 y.o. with moderate RCM.

Pre-study (run-in): 30 moderate to severe headache days

1st month (active): 28 moderate to severe days

2nd month: 30

3rd month: 30

4th month: 26

5th month: 29

Midas: pre-study=25, post=12

Beck depression: pre-study=3, post=3

Beck anxiety: pre-study=10, post=10

QOL: pre-study=10 unhealthy days, post=6

Summary: the # of moderate to severe headache days decreased from 30 pre-study to 27.5 (average of 4th and 5th month). Midas disability improved.  Depression was low, and did not change. Anxiety remained unchanged. The # of unhealthy days improved.

Patient #7  24 y.o. M with severe RCM

Pre-study (run-in): 30 moderate to severe days

1st month (active) and months 2 thru 5: 30 moderate to severe days each month

Midas: pre-study=210  (post-study not done)

Beck depression: pre-study= 27  (post-study not done)

Beck anxiety pre-study= 22   (post-study not done)

QOL: pre-study=27 unhealthy days  (post-study not done)

Summary: the # of moderate to severe headache days did not change (30 days per month). This patient did not complete post-study surveys. Pre-study his Midas revealed high disability. Depression and anxiety were significant.

Patient #8: 64 y.o. F with severe RCM.

Pre-study (run-in): 19 moderate to severe headache days(and 6 mild days)

1st month (active study): 22 moderate to severe days

2nd month: 20 moderate to severe days

3rd month: 17

4th month: 22

5th month: 20

Midas disability: pre-study=23, post=26  (post-study not done)

Beck depression: pre-study=26  (post not done)

Beck anxiety: pre-study=21  (post not done)

QO: pre-study=30 unhealthy days  (post not done)

Summary: The # of moderate to severe headache days increased slightly by the 5th month. Disability, depression, and anxiety levels were high (post-study surveys were not done). Pre-study every day of the month was an unhealthy day.

Patient #9:  34 y.o. F with severe RCM

Pre-study (run-in): 21 moderate to severe headache days(and 9 mild days)

1st month (active study): 21 moderate to severe days

2nd month: 19

3rd month: 22

4th month: 23

5th month: 23

Midas disability: pre-study=42, post-study=30

Beck depression: pre-study= 0, post=0

Beck anxiety: pre-study=3, post=2

QOL: pre-study=24 unhealthy days, post=23

Summary: the # of moderate to severe headache days were slightly increased by the 5th month. Disability improved somewhat. There was no depression, and mild anxiety was unchanged.  The # of unhealthy days was essentially unchanged.

Patient #10:  62 y.o F  Severe RCM.

Pre-study:  moderate or severe headache days: 30

This patient did ingest the eggs but no headache data was captured.

Patient #11: 39 y.o. F  Moderate RCM.

Pre-study: moderate to severe headache days: 30. This patient ingested only one dose of the eggs. She subsequently had GI upset and mild diarrhea. She discontinued the therapy. Over the ensuing 4 months, the GI upset and diarrhea improved but did not resolve. GI work-up was pending. The headaches remained unchanged.

Lab tests/ECG:  blood tests were drawn prior to the study, and after the 3rd month. There were no abnormal tests that resulted from the treatment. ECGs did not reveal significant abnormalities.

Summary of Results

5 of 11 patients met the primary endpoint (a reduction in moderate or severe headache days by at least 3 per month). The number of moderate or severe headache days decreased by 14, 10, 8, 7, and 3 in these patients.

The patients who met the primary endpoint all began with essentially no clinical depression at baseline.  Disability declined in all 5 patients, as did anxiety. Quality of life (number of unhealthy days per month) improved in 2 patients and remained the same in 3 patients.

4 of 11 patients did not meet the primary endpoint. 1 patient did not supply data, and another discontinued due to diarrhea. Analysis of their secondary endpoints did not result in any definitive conclusions as to why they did not have a successful trial.


Eleven patients with refractory chronic migraine were enrolled. Five patients met the primary endpoint.  The 5 patients experienced a decrease in moderate to severe headache days per month of 14 days, 10 days, 8 days, 7 days, and 3 days. Four of the remaining patients finished the study but did not incur any benefit.  One patient did not provide data, and another discontinued the eggs due to diarrhea.  That was the only adverse effect observed in the trial.

The 5 patients who experienced a decrease in the number of moderate to severe headaches also observed a significant lessening of disability. All of these 5 patients had low baseline depression scores.

This was a small open label study that included patients with refractory chronic migraine. They ingested helminth eggs for 5 months. The purpose of the eggs was to downregulate the immune response. Helminths may modulate the immune system via release of excretory/secretory proteins. The cell mediated inflammation may be modulated by the helminth eggs. While the helminth eggs modulate immune activity, there has been no evidence for harm. Tdhe concept of migraine as an autoimmune illness, or at least involving the immune system, has been debated and discussed for decades.1 This study is rooted in evolution. For millions of years the GI tract of primates (and other animals) has been colonized by various worms or other parasites.  It has only been recently, in the past hundred years, that helminths and other parasites have been eradicated from human GI tracts.  This has been accomplished through improved sanitation as well as the introduction of clean water and food.

The role of helminth therapy has been discussed in the introduction section (above).  The studies have involved introducing helminth eggs into patients suffering from various autoimmune illnesses.  

There have been 12 helminth therapy studies conducted for various autoimmune diseases9,10,11,15.  The use of helminthes for various autoimmune disorders has met with reasonable success, with minimal adverse effects. The study on Inflammatory Bowel Disease (IBD)9,10,12 revealed that this may be a viable therapy, and that the eggs appear to be safe.  A study on Type 1 Diabetes Mellitus (T1DM) 16,17 also indicated that the eggs are safe for human consumption. This was also confirmed in a study involving the eggs and Systemic Lupus Erythematosus (SLE)12,13,18.  

Conclusion: This small study indicates that there may be a role for helminth therapy in the treatment of refractory chronic migraineurs. This approach is rooted in evolution. We ignore evolution at our peril. For millions of years helminths and other parasites have populated the GI tract of animals. The presence of helminths results in a downregulation of certain aspects of our immune system. By re-introducing helminths into the GI system, we may dampen our immune response. This may aid in the treatment of migraine headache.  A randomized, placebo-controlled trial would be welcome.


Diana Delatre was the study coordinator. The Tanawisa Company donated the eggs for the study. Other than donating the eggs, the company did not play a role in the study.  

Conflicts of interest: none

NOTE: This therapy could be helpful for long haul Covid symptoms, if studies revealed sufficient efficacy…


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The Bipolar Spectrum In Pain Patients: Recognition and Management

Olivia Lee and Lawrence Robbins, MD

Introduction to Bipolar Disorder

The broadening concept of the bipolar spectrum has evolved over the years. We no longer view bipolar primarily as characterized by mania. Bipolar disorder is a chronic psychiatric illness that is broadly categorized in the DSM-V into several subtypes – bipolar I and bipolar II – depending on the presence of depressive, manic, or hypomanic features. It may occur in at least 4.4% of the population, but this number is likely to underestimate the true prevalence.1 There are major issues in identifying the milder bipolar presentations.2 Bipolar disorder often co-occurs with other psychiatric illnesses, creating innumerable patient presentations that may not fit neatly into the boxes of the two subtypes. The word “bipolar” is misleading and creates a stigma of severe mental illness.  There certainly is underdiagnosis for the milder forms. Most patients do not suffer from classic manic symptoms. The milder “hypomanias” are subtle and mild in comparison to true mania. For most patients there is a significant lag time from the onset of milder bipolar symptoms and diagnosis.

The classic mania that defines bipolar I is easily recognized.  Symptoms of mania include euphoric mood, grandiosity, distractibility, flight of ideas, thoughtlessness or risk-taking, and excessive involvement in pleasurable activities (i.e., sex, gambling, spending). Patients in the midst of a manic episode may also take on an excessive number of activities and exhibit pressured speech, excessive speech, irritability, and insomnia.3 These behaviors cause serious impairment to daily functioning and often last for several days or longer. Acutely manic patients are also high risk for harm to themselves or others.4

Milder hypomania is less likely to impair everyday functioning. However, it is also hypomania that is more commonly missed for a variety of reasons.4 Hypomania and the milder end of the bipolar spectrum have various presentations, complicating the diagnosis. These patients may have persistently agitated personalities, with frequent depression or excessive energy but not meeting the classic diagnostic criteria for bipolar I or bipolar II. Brooding, irritable pessimism may be a manifestation of the milder end. They often have a family history of bipolar disorder or depression. Many do not identify or remember a clear hypomanic episode. Diagnosing and treating these patients greatly improves  quality of life and reduces mortality risk from suicide. The clinical stakes for missing bipolarity are enormous.

Speaking with a “significant other” is vital for teasing out mild hypomanic symptoms.4 Most patient simply complain of depression. Signs of mild bipolar disorder may include a history of early onset depression(prior to age 18), severe bouts of depression, rapid onset depression for no apparent reason, poor response to trials of antidepressants (including complaints of being up all night, mind racing, etc.), agitation, anger, high anxiety, hypersomnia or (less likely) insomnia, and irritability. Family history of severe depression, hospitalization, and other bipolar traits is helpful. The “bipolar reaction” to antidepressants may give insight into underlying bipolar disorder.4 Family history of a bipolar reaction to antidepressants may also be a clue. An opposite reaction to other drugs may be present, such as being anxious or wired from benzodiazepines or sleeping pills. Depression is often the primary problem in bipolar II disorder; it is much more pervasive than are the highs of hypomania. Comorbid moderate or severe anxiety may further compound impairment seen in bipolar depression and increase suicidal tendencies by up to 35%.5 Suicide and substance abuse are commonly found among those with untreated bipolar.

Comorbidity of Chronic Pain and Bipolar Disorder

Bipolar disorder patients who also suffer from chronic pain are challenging. Almost 24% of bipolar patients may present with chronic pain.6 The comorbid pain decreases quality of life. Patients with bipolar disorder and chronic pain often respond poorly to treatment and have an increased risk of suicide.6 One study that assessed the relationship between pain and bipolar disorder recommended a pain assessment as part of the routine care for patients suffering from bipolar.6  It requires a multidisciplinary approach to adequately treat these patients. Other than the pain physician/provider, psychotherapists constitute a vital part of the team.

Comorbidity of Migraines and Bipolar Disorder

The comorbidity of migraine with mood disorders has been well documented.  There have been a number of clinic based studies as well as epidemiologic samples from community populations.7 Migraine and depression share some of the same pathophysiology.  Antidepressants or mood stabilizers may alleviate both conditions. In the majority of migraine patients who suffer from depression, anxiety is a complicating factor. The anxiety disorder often precedes the age of onset of migraine, with depression following afterward. Migraine or other pain may exacerbate depression, and depression fuels migraine and pain.  This is in addition to the shared environmental and genetic factors linking migraine and depression.

Emerging data is identifying the relationship between bipolar disorder and migraine. From 25 to 35% of bipolar patients suffer from migraine as well.6  This association may be due to shared pathophysiologic mechanisms.

Treatment Approaches for Bipolar Disorder

It may take some time to find the effective medication, or medications, for a given patient. Mood stabilizers often are the mainstay of treatment, and sometimes help the  headaches. The anticonvulsants, lithium, and the atypicals constitute the 3 classes of mood stabilizers. Lamotrigine is the most commonly used antiepileptic for bipolar, but does not help headaches. Lamotrigine may be beneficial for some with neuropathic pain. Divalproex sodium is effective for mania, hypomania, depression associated with bipolar disorder, and for migraine prevention. Divalproex has been well studied for these conditions and is one of the most commonly used migraine preventives. Carbamazepine and oxcarbazepine are antiepileptics that have utility as mood stabilizers, but not for migraine prophylaxis. They may alleviate neuropathic pain. Oxcarbazepine is somewhat safer than the original carbamazepine. Gabapentin has been effective in high doses for some patients with milder bipolar symptoms. Gabapentin is effective for certain pain syndromes, but not for migraine.

Lithium carbonate is an underutilized mood stabilizer. Low doses of lithium do not usually cause hypothyroidism or irritate the kidneys. With appropriate monitoring these risks can usually be avoided.  Lithium sometimes alleviates cluster headaches.  Lithium has also been evaluated for conditions such as multiple sclerosis and Alzheimer’s.8

Divalproex sodium, carbamazepine, and oxcarbazepine may produce teratogenic effects. Divalproex is more likely than the others to result in birth defects, particularly at doses above 500mg daily. Lamotrigine may be the best choice of an antiepileptic during pregnancy.  Lithium taken during pregnancy is fetal cardiac anomalies, but this is rare.  Lithium may be indicated for bipolar during pregnancy disorder under appropriate circumstances.8–10 For women who were stable on lithium prior to pregnancy, discontinuation during pregnancy may lead to relapse.10

Atypical antipsychotics are also a mainstay for bipolar symptoms.11 These agents include the general categories of “pines”, “dones”, “pips” and “rips”. These include clozapine(the first atypical), olanzapine, quetiapine, risperdone, lurasidone,  brexpiprazole, aripiprazole, and cariprazine.These are efficacious in treating mania and are prescribed as monotherapy or in combination with another mood stabilizer.12 The atypical side effects are many and varied. These include metabolic syndrome (insulin resistance, dyslipidemia, hypertension), weight gain, fatigue, “brain fog”, and extrapyramidal symptoms (akathisia, acute dystonia, dyskinesia/parkinsonism, and tardive dyskinesia).13 Patients on atypical antipsychotics  should receive routine bloodwork.  Signs of EPS may go unnoticed by some patients, rendering it important to ask specific questions. There certainly are concerns about the atypical antipsychotics during pregnancy, but in low doses these have resulted in minimal problems in the newborns.

As previously mentioned, lamotrigine is a very commonly prescribed mood stabilizer for bipolar disorder. It is one of the only effective medications for bipolar depression.14 Initiating a patient on lamotrigine requires a slow titration due to the rare (1:3,000: according to the German rash registry) but lethal side effects of Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).15 SJS/TEN are variants of the same hypersensitivity reaction, differentiated by the percent of skin surface area that is affected (<10% in SJS, >30% in TEN). This rare rash is characterized by painful blisters, peeling skin, and tissue necrosis. The SJS rash often occurs in unusual areas, such as the palms of the hands, soles of the feet, or mucous membranes. A “regular” drug rash may occur in up to 10% of patients. Signs of SJS/TEN typically occur within 8 weeks of initiation and warrant immediate discontinuation of lamotrigine.15 Many of the anticonvulsants carry the risk of SJS/TEN, such as divalproex, carbamazepine, and oxcarbazepine.


Patients with bipolar spend the vast majority of their time in depression rather than in mania. Many of these patients require combination therapy to target depressive symptoms. Lamotrigine and quetiapine are two of the atypicals that may be effective in managing depressive episodes.16 While lithium is a first line therapy for mania, it has also shown efficacy in preventing relapse of depressive episodes and decreasing suicidality.16 Combination therapy of olanzapine and fluoxetine has been approved by the FDA for treating depression associated with bipolar I disorder.16 Lurasidone is an atypical that has shown promise for the depression.4,17 Antidepressants usually result in either no effect, or the typical “bipolar” response (up all night, wired, mind racing). Occasionally they are helpful. Emerging therapies include, among others, ketamine, TMS, and microdosing (primarily psilocybin).16


It is crucial to recognize psychiatric disorders in our pain patients. Patients with unrecognized personality disorders or bipolar disorder often suffer from poor outcomes. Patients with the milder end of the bipolar spectrum frequently are diagnosed and treated as if they suffer from “regular” depression. They generally do not do well on antidepressants.  Patients with psychiatric comorbidities, such as bipolar, require a multidisciplinary approach. The medications that treat psychiatric conditions may also be helpful for the pain conditions as well.


Olivia Lee is a fourth year medical student at Des Moines University. Her clinical interests include the interface of psychiatry and neurology. Lawrence Robbins is an associate professor of neurology, Chicago Medical School. He is in private (neurology and headache) practice in Riverwoods, Illinois. Lawrence has contributed to 390 articles/abstracts and written 5 books (on headache). Address correspondence to Lawrence Robbins at


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President’s Message: Running Headlong into what You Thought Was Behind You

Harry J. Gould, III, MD, PhD

With the FDA’s blessing in mid-December on the administration of vaccines for COVID-19 and subsequent indications of downward trends in the rate of infections, hospitalizations and deaths associated with the virus came a feeling that the worst of the pandemic was past and we were on a return path to recover normalcy. Even with large numbers of individuals that chose not to be vaccinated, the falling numbers reflecting the impact of disease were encouraging and many businesses, organizations, and individuals began to abandon mitigation practices, i.e., social distancing and masking, and began returning to former practices and patterns of behavior. In-person visits in clinical practice began to replace the virtual platforms and we were again able to apply our mitigating strategies for reducing medication misuse, abuse and diversion, thereby lessening some of the provider’s anxiety associated with the impaired ability to identify potential problems related to opioid management.

Indeed, the Southern Pain Society’s (SPS) planning committee for the 2021 Annual Meeting, upon reviewing the trends in societal response to the vaccines, was cautiously optimistic and was looking forward to being able to hold our annual meeting in-person. Despite the committee’s best efforts to plan and deliver an informative and thought-provoking meeting that might also serve as an indicator that we were on the mend, the trend in disease statistics foreshadowed a lack of support for these efforts.  Due to the establishment and spread of variants of COVID-19 in the population, the rate of infections, hospitalizations and deaths shifted and by mid-August had returned to, and in many places surpassed, levels that had been recorded at the peak of the first wave of the pandemic.  By the late August, elective procedures and in-person appointments in clinics were again being replaced by virtual visits.  As a professional organization, the SPS could no longer be reasonably certain about ensuring individual safety for our participants, chose not to put individuals at risk of becoming seriously ill and postponed the 2021 meeting; perhaps a fortuitous decision in light of the additional complications imposed by Hurricane Ida.

The distractions of the last 18 months have emphasized the importance of maintaining and expanding efforts to improve patient safety and reliably delivering appropriate and effective care even in the face of adversity. As the pandemic continues, the SPS is expanding efforts to maintain and offer new opportunities to share ideas and express concerns, challenges, and potential solutions for the challenges facing our patients and practices. In offering opportunities to support scholarly activity and communication, like the recent virtual forum for abstract presentations.  We hope to encourage those with the wisdom and experience accrued through years of experience and those new to the field of pain medicine to come together and share ideas and experiences and hopefully create a forum for inquiry that will foster the pursuit of a better understanding of complex condition we strive to treat; its proper assessment; and optimal treatment options supported by evidence necessary for making the most appropriate management decisions.  I encourage you to follow our newsletter and postings on social media for opportunities as we continue to monitor the pandemic and set our sights on the future when we will be able to meet again with the pandemic behind us, even stronger than before.