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President’s Column July, 2020–Virtual Annual Meeting

Ann Quinlan-Colwell, PhD, RNBC, DAAPM

Last year we began planning our 2020 Southern Pain Society meeting,  “Perspectives, Concerns and Options for Managing Pain.”  Little did anyone realize that national events of 2020 would necessitate many concerns and needs.  We have worked to change our perspective as we explored options for safely coordinating an exciting conference to share timely and innovative pain management information.  Interestingly, in numerology, 20 is related to service and teamwork.  There is no doubt that the conference planning committee definitely exhibited a double effort of service and teamwork as they planned, evaluated, re-planned, explored options, re-evaluated, and redesigned this conference.

It is my great pleasure to share with you that the 2020 SPS conference will continue with the agenda topics and speakers planned.  We will be using a virtual format starting on November 13 and 14 and re-connecting again next March 12 and 13.  The virtual option allows for us to schedule shorter days at different times to avoid “Virtual Fatigue.”

The amazing presenters will discuss managing chronic pain throughout the continuum using pharmacological and nonpharmacological interventions for all types of pain including musculoskeletal and neuropathic pain.   A variety of measures will be presented, ranging from spinal cord stimulators and intrathecal treatments discussed by Eric Royster, MD, to acupuncture and Chinese herbal medicine presented by Arnuad Versluys, MD.  George Singletary, MD will explore all the uses for buprenorphine and Todd Sitzman, MD shares the current pharmacological and interventional therapies for managing osteoarthritis of knees. Miroslav Backonja, MD will review new pharmacological options for managing neuropathic pain.  Jonathon Cole, PhD will examine the reciprocal relationship between sleep and pain and Perry Fine, MD will share the lessons learned and explore the current needs and future opportunities for palliative care. Cases will be presented in which some of these options will be explored.

From a more universal perspective Rollin Gallagher, MD will share with us the back story of the HHS Pain Task Force Report and Scott Fishman, MD will update those attending about the guidelines and regulations for opioid prescribing.  Esther Bernhofer, PhD will share the ethical perspective of really doing the right thing for patients living with pain.  In a very timely session, Jay Kaplan, MD will discuss burnout and resiliency.   We are planning to have our traditional poster session and vendor exhibits.

No one ever wants to postpone a visit to New Orleans and while we regret not being able to connect with you in person in NOLA we certainly look forward to sharing the conference with you virtually.  There truly is something for everyone.  An innovative and fun addition to the conference this year will be the option to take a Virtual Historical, Architectural Walking Tour of the French Quarter guided by our own Dr. Randy Roig.  It will definitely be educational, entertaining, and fun!

Please save the dates and plan to connect with us virtually in November and next March. Please check our website for dates, times and registration options.

Cluster Headaches and Treatment Update

Lawrence Robbins,M.D.*

Summary of cluster headache characteristics and update on abortive and preventive treatments.

Cluster headache is among the most severe pains known to mankind. It is characterized by excruciating, debilitating pain lasting from 15 to 180 minutes, or occasionally longer. The pain is usually located around or through one eye or on the temple. The series of cluster headaches usually lasts several weeks to several months, once or twice per year. Clusters may occur every other year, or even less frequently. Several of the following are usually present: lacrimation, nasal congestion, rhinorrhea, conjunctival injection, ptosis, miosis of the pupil, or forehead and facial sweating. Nausea, bradycardia and general perspiration also occur in many patients. Attacks usually recur on the same side of the head. Cluster headaches tend to occur more in spring and fall. There is usually no family history of cluster headache, but occasionally there is such a family history.

Specific Characteristics of Cluster Headaches

Males are afflicted more than females by a 2.5 to 1 ratio. The onset of the clusters is usually between the age of 20 and 45, but there are many cases of clusters in teenagers and occasionally clusters begin in the 50s or 60s and rarely in the 70s. Women tend to have an older age of onset for their cluster headaches than men. Occasionally a brief aura may occur. The prevalence is 0.4% of the population.

The pain of the cluster attack is extreme and starts very quickly, usually without an aura or a warning. Within minutes, it becomes very severe. Although the pain is usually located about the eye or temple, it may be more intense in the neck or facial areas. Although usually unilateral, the pain changes sides in 10% to 15% of patients—either during a cluster cycle or the next cycle may see pain on the opposite side. The pain itself is excruciating, described in various manners as sharp, stabbing—“like my eye is being pulled out” and occasionally, throbbing.

The length of attack varies, but 45 minutes is the average. Cluster patients usually experience one or two headaches per day, but this may increase to as many as seven per 24 hours or decrease to as little as one or two per week. They usually occur around the same time each day, with the time period 9 pm to 10 am being the most frequent. Approximately half of the patients awaken from sleep with the headaches.

Cluster cycles, except in the chronic variety, usually last 3 to 8 weeks and then stop until the next bout of clusters. The clusters occasionally last as little as several days, or as long as 5 months at which time we begin to think that they may have converted to the chronic cluster type. Ten percent of cluster patients have chronic clusters in which there is no break of at least six months between attacks. One or two bouts of the clusters per year is average for most patients. They may increase in frequency with only several months in between bouts or several years may elapse between attacks. When periodic clusters begin at older ages, the chance of conversion to chronic cluster becomes greater. The natural history of clusters is not known, but the tendency is for the cluster series to stop at a certain age. Many patients “lose” their clusters in the late 30s or 40s, particularly if they have had them for many years.

During the cluster series, over half of the patients are very sensitive to alcohol and most patients will have an attack triggered by ingestion of alcohol. The other ‘headache foods’ are less important, but avoiding MSG, aged cheeses and meats, and chocolate is prudent during the cluster series. MSG, in particular, seems to trigger a more sever cluster in some patients. Cluster patients may have their clusters after stress is over and occasionally excessive cold, heat, or bright light have been associated with the precipitation of a cluster. However, most cluster patients have very little control over the clusters, except with medication.

The typical episodic cluster series builds over one to two weeks and peaks for one to three weeks and then decreases. In the 10% of cluster patients with chronic clusters, periods of peaks and valleys with the headaches also occur but an extended break without any clusters is not present. Chronic clusters are not usually consistent throughout the year but tend to increase in certain seasons. In managing the clusters, we keep in mind the fact that the clusters build and then peak so that I often treat them with somewhat less medication—particularly corticosteroids—in the beginning of a cluster period. The natural history of clusters is unknown. However, it appears as if the more years a patient has them, the more likely they are to abate.

Non-Medication Treatment of Cluster Headache

Other than medication, very little is available for sufferers of cluster headache. The pain is too severe for relaxation methods and some patients state that biofeedback or relaxation may actually precipitate or increase a cluster. However, learning simple deep breathing techniques or relaxation methods does aid some patients in helping to curb the anticipation of the cluster attacks. Much anxiety is generated during the day when the patient knows that nighttime brings intense, excruciating pain.

Icing the area of pain may help, although sometimes heat will be more effective. Some patients let the shower run hot water on their cervical area, or they use a shower water massage apparatus to allow the hot water to run over their cervical or frontal area. Pressing over the temporal area with moderate pressure is occasionally helpful. Cluster patients usually feel better when moving about during an attack. They tend to be active (such as pacing) as opposed to the quiet sought by migraineurs.

Medications For Cluster Headache

For most patients, both abortive and preventive medications are helpful and only in a minority of situations do we simply use abortive medicines.

The abortive treatment for clusters is the same for episodic and for chronic cluster headaches. Since the headache is very intense from the beginning and the pain is severe and excruciating, medication to aid the attack must act quickly. Most cluster attacks last less than one hour, averaging about 45 minutes, and thus oral pain medication is only of limited value. However, in patients whose attacks do last for more than one hour, pain medications may be useful—particularly if the standard cluster abortives are not completely effective. Anti-emetics are also used for those patients with nausea, and the sedative effect of these is often helpful.

First-Line Cluster Abortive Medications

The first line abortive cluster medications are as follows:

  • Inhaled oxygen(higher flow rate is much more effective)
  • Sumatriptan injections(3mg and 6mg available)
  • Imitrex® (sumatriptan generic is available) or Zomig® (zolmitriptan) nasal spray

Oxygen. Oxygen is effective in approximately 70% of cluster headache patients. To obtain a small tank with a mask is relatively easy and not terribly expensive. The tanks are usually rented for one month. If feasible, most patients with cluster headaches should attempt to use oxygen for their attacks. The patient should be sitting with the body leaning slightly forward. A mask is used and 100% oxygen is inhaled at 12 to15 liters per minute. In healthy patients with no pulmonary problems, the oxygen may be inhaled for 15 to 20 minutes. A rebreather mask is helpful.

Sumatriptan Injections. Injectable sumatriptan (Imitrex®, Zembrace=3mg epi-pen device, or the generic: pre-filled syringes, vials(draw up in an insulin syringe), Stat dose system) is generally effective. Sumatriptan pills are more helpful for migraine than for cluster headache, but oral triptans are occasionally adequate. Many patients are reluctant to give themselves injections but, for those who are willing, injected sumatriptan is usually effective—often within minutes—and with a minimum of side effects. Oxygen may be used in conjunction with sumatriptan, and escape pain medication may also be utilized. The new gepants are not indicated for cluster, and generally take too long to become effective.

The dosage of sumatriptan is usually 3 to 6mg given subcutaneously at the onset of the cluster headache. A repeat dose may be given at least one hour after the first injection. Two 6mg injections, or 12mg, is the maximum recommended dosage per 24 hours. Sumatriptan is administered subcutaneously by the use of a convenient auto-injector device. Sumavel™ DosePro™ is a ‘needle-free’ sumatriptan injection.  While Sumavel is convenient, it still does sting, and may bruise quite a bit. Also, vials of sumatriptan are available for use with an insulin syringe. By using the vials, the dose may be titrated(some cluster patients only require 3 or 4mg).

Daily use of sumatriptan has not been studied extensively. Thus, until further studies are known, prudent use of sumatriptan would dictate that no more than six injections per week be taken for cluster headache (less for migraineurs).

The side effects of sumatriptan are generally less than those with dihydroergotamine (DHE). Transient pain at the site of injection is common, and ‘icing’ the injection site prior to use may decrease this burning pain. Other side effects include tingling sensations, disturbances of taste, heat flashers, and feelings of pressure or heaviness. Side effects tend to be short lasting. Chest symptoms, flushing, dizziness, and overall weakness may also occur. Minor transient increases in blood pressure have been seen. Nausea is relatively common. Sumatriptan should not be used in children, in pregnant women, in the presence of hepatic or renal impairment, or with cardiovascular disease. Patients over the age of 45 should be screened for cardiac risk factors. The frequent chest pressure that occurs is not usually felt to be of cardiac origin.

Sumatriptan or (Zomig)zolmitriptan nasal spray: while not as effective as the injection for cluster headache, the nasal spray is very convenient and many patients prefer this route of administration. We usually limit the sprays to two per day, but for cluster headaches we will occasionally utilize a third spray as well. Of the two nasal sprays, Zomig nasal spray 5mg is more effective than the sumatriptan spray.  There is a 2.5mg Zomig nasal spray available, but the vast majority use the 5mg spray. While not as rapidly effective as the injections, the nasal spray works faster than triptan tablets. Speed is essential in relieving cluster headache, yet occasionally patients prefer the oral triptans.

Second-Line Cluster Abortive Medications

Second line therapies include oral triptans, ergots and dihydroergotamine (DHE), Cambia, ketorolac nasal spray or injections, oral pain medications and intranasal lidocaine.

Oral Triptans. Any of the oral triptans may help, but are usually too slow for cluster headache. Sumatriptan 100mg is the most commonly used oral triptan. The two slow-acting triptans, frovatriptan and naratriptan, are not usually used acutely for clusters. Occasionally, these longer-acting triptans are utilized, mostly at night, to prevent nocturnal clusters.

Ergotamine Tartrate. Strong vasoconstrictors, the ergotamines have many limitations. Ease of administration (they are available as tablets) is a major advantage of the ergots. The frequent side effects of nausea and nervousness limit their use. In older patients, the risk of angina or an actual myocardial infarction restricts its use. The rebound headaches that occur in migraineurs do not seem to be as prevalent a problem in cluster headache patients. The primary ergotamine preparations are generic Cafergot® pills, suppositories and Ergomar® sublingual pills. Peripheral vascular disease or hypertension are contraindications. Ergotamines may exacerbate peptic ulcer disease. The effective dose of ergotamine varies widely among patients. Ergots may be combined with the use of oxygen and other abortive measures but not with triptans.

Ergomar. Tablets contain 2mg of ergotamine tartrate with no caffeine. The usual dose is one pill sublingually at the onset of the cluster attack. Ergomar may also be swallowed and this route may be just as effective as the sublingual method. This may be repeated once in one or more hours and limited to two pills per 24 hours. Nausea is a common side effect as is a bitter or “bad’ taste in the mouth. Nervousness is a frequent side effect, but less so than with Cafergot because there is no caffeine in Ergomar. Ergotamines need to be used with great caution in the presence of hypertension, peripheral vascular disease, or peptic ulcer disease. If chest symptoms occur, ergots should be discontinued.

Generic Cafergot (only generic available). Consists of 1mg of ergotamine tartrate and 100mg of caffeine. Cafergot pills are the most convenient but least effective of the ergots. Dosage is one or two pills at the onset of headache, repeated every two hours as needed, with a maximum of four per day and ten per week. Side effects are similar to the preceding Ergomar discussion, with nausea and nervousness being common. Because of the caffeine, anxiety or nervousness is more common with Cafergot pills than with Ergomar. The same precautions discussed above in the Ergomar section also apply to Cafergot.

Compounded Cafergot Suppositories (only compounded available). These are less convenient but much more effective than the pills. Cafergot suppositories contain 2 mg of ergotamine tartrate and 100 mg of caffeine. The primary side effects are nausea and anxiety. The initial dose is one third or one half of a suppository and then the dose is titrated up or down, depending on the patient’s response. The dose may be repeated after one hour, up to a maximum of two suppositories per day and five per week. Some patients find that as little as one fifth of a suppository is all that they require. Side effects of Cafergot suppositories are the same as those of Cafergot pills. Nausea and anxiety always are limiting factors in the use of ergots.

Compounded Cafergot PB suppositories (only compounded available). These are similar but more effective than plain Cafergot suppositories. Cafergot PB contains 2 mg of ergotamine tartrate, 100 mg of caffeine, 60 mg of sodium pentobarbital, and 0.25 mg of 1-alkaloids of belladonna. Dosage is the same as for the plain Cafergot suppositories. Side effects are decreased, with less nausea and nervousness. Sedation may be a problem, however.

Dihydroergotamine (DHE). This is different from the other ergots in that it is primarily a venoconstrictor rather than an arterial constrictor. Since 1945, there have been relatively few serious side effects reported. DHE is available as an intramuscular (IM) or subcutaneous (SQ) injection or as a nasal spray (Migranal®). The usual dose is 1 mg IM or SQ, or one spray in each nostril to be followed in 10 to 20 minutes by one further spray of Migranal in each nostril. Side effects tend to be minimal with DHE, but nausea, a heat or flushed sensation, nasal stuffiness from the spray, or leg cramps may occur. Occasionally, chest heaviness is also seen. While DHE is not as effective as sumatriptan for cluster headache, DHE at times is the best alternative in patients who may be at some risk for cardiac disease. However, if patients have major risk factors such as uncontrolled hypertension or have known atherosclerotic heart disease, then DHE must be avoided. The usual maximum is three injections per day or two nasal sprays in each nostril per day. A new inhaled form of DHE is expected to be approved shortly. The inhaled form will have better efficacy than the Migranal spray, but not as effective as the injections.

Cambia. Cambia is a powdered form of diclofenac potassium, 50mg. Cambia is FDA approved for migraine. The usual dose is 1 packet(with water, or apple juice) every 2 or 3 hours as needed. GI side effects may limit use. Cambia may be combined with a triptan. Cambia has a quicker onset of action than tablets of nsaids.

Ketorolac nasal spray(Sprix) or ketorolac injections. Sprix is a nasal spray of ketorolac, faster acting than tablets but not as powerful as the injections. Sprix is relatively well tolerated; the usual side effects include a feeling of burning in the throat, and GI side effects.  The ketorolac injections, 30 or 60mg, are effective for many migraine and cluster sufferers.  GI and renal concerns limit use with ketorolac. Ketorolac should be limited to 6 doses per week. s

The abortive analgesic medications include, among others,  the following;

  • Extra Strength Excedrin®
  • Butalbital compounds (Fiorinal®, Fioricet, Esgic®, Phrenilin: all are available as generic)
  • Opioids

In general, we do not want to have cluster patients rely on butalbital or opioids. However, in some refractory patients the pain is so severe and the other therapies are ineffective, justifying the use of butalbital or opioids.  The milder approaches, such as Excedrin, should be utilized first, then the butalbital compounds or opioids. While rebound or withdrawal headache is less of a concern with cluster than migraine, we still must try and limit the abortives. At times, this is not an easy task.

Lidocaine spray.  There are various devices for SPG blocks(Tian360, Sphenocath) used as a 4% lidocaine solution, the spray has been used since the mid-1980s for cluster headache. I have found it only mildly effective for most patients and almost never adequate by itself. However, intranasal lidocaine does provide sufficient relief to warrant its use. Lidocaine is very safe,  with minimal side effects. When used in conjunction with ice and one of the first-line abortives, the lidocaine spray may add 10 to 30% relief.

I put 4% topical lidocaine in a plastic nasal spray bottle. The patient is then instructed to lie in the supine position, extend their head back 30 to 45 degrees, turn the head toward the side of the pain and spray two or three sprays of the lidocaine intranasally. This may be repeated, but I usually limit the lidocaine sprays to six or eight in a 24-hour period. If the nasal passage is blocked, several drops of 0.5% phenylephrine may be used prior to the lidocaine.

Alternatively to the spray bottle, 1 ml of 4% topical lidocaine may be slowly dropped, via a dropper, into the nostril on the side of the pain. Side effects are minimal and may include numbness in the throat or, rarely, nervousness or tachycardia.

Another option for home use is to utilize a TB syringe, with lidocaine, and an atomizer. This is inexpensive.

Preventive Medications(see table 2)

Each cluster patient is unique, with a number of variables determining where we go with medications. If a patient has a short episodic cycle, we may just use abortives, or cortisone plus abortives.  For longer cycles we want to initiate one of the usual preventives, such as verapamil. Chronic cluster patients usually require daily medication for most of the year.  Most often, we use cortisone(usually Prednisone) for a short period of time, while initiating another preventive, such as verapamil.  Prednisone, while usually very effective,  should be limited; we want to minimize cortisone side effects. There is some evidence that cluster sufferers may be slightly more prone than others to femoral head necrosis from cortisone.

Comorbidities often determine where we go with medications. If a cluster sufferer is older, smokes, has HTN and reflux, we will be limited as to our medications.  Age, GI problems, psychiatric conditions, and previous reactions to medications all contribute to our medication decisions. For those with chronic clusters, we want to utilize medications that have minimal long-term side effects.  Table 2 summarizes the usual preventive approaches to preventing cluster headaches.  For quick relief, occipital injections with bupivicaine and/or cortisone may be effective. Frontally, the SPG blocks, with bupivicaine, often are helpful for frontal chronic migraine, and cluster headache. They are done via the newer Tx360 device, or the SphenoCath device. SPG blocks, with one of these devices, are very safe, and only take minutes to administer.

Refractory Clusters: For those cluster sufferers who have not found relief with the usual ministrations, a number of approaches have been utilized.  Emgality, a monoclonal antibody used for migraine prevention, is now approved for episodic cluster(300mg once per month). Unfortunately, because of the small numbers in limited studies, evidence is lacking for many refractory approaches. These approaches include: stimulants(methylphenidate, mixed amphetamine salts), melatonin, testosterone, SPG blocks, daily opioids, daily triptans(used as a preventive), daily ergots(rarely used),  botulinum toxin, and psilocybin, among others.  There are several cluster headache support groups, such as Clusterbusters.  Clusterbusters runs an excellent annual meeting of cluster headache sufferers.

I have found daily triptans(usually 1 at nite, as a preventive) to be helpful for some patients. The longer-acting triptans, frovatriptan and naratriptan, are usually used for use on a daily basis.  SPG blocks are easy to administer with the newer devices(Tx360 and SphenoCath), and used 2 to 4 times weekly they can be very helpful.  For some refractory chronic clusters, the implantable ATI SPG stimulator may be very helpful;  this is being utilized at several centers in Europe, and studies are ongoing in the U.S.  As a last resort, opioids may at least alleviate some of the suffering.  Psilocybin(illegal in the U.S.; we cannot advocate its use) has had some research behind it, and has been helpful for some patient

 Sample Case History

Richard is a 40-year-old man with a history of 4-week long cycles of cluster headaches, occurring once a year in the fall. The headaches began when he was 35. The cluster period begins slowly, increasing over one week’s time and reaching a peak where Richard has 2 or 3 severe attacks per day. These occur during the night from 10 pm to 3 am. Each cluster attack lasts from 40 to 90 minutes, and the pain is severe. The headache is always on the right side, and is accompanied by eye tearing and nasal congestion.

Treatment Plan

Richard visits our office during the first week into his 4-week headache series. The headaches are increasing in intensity and he is miserable from the pain. At this point, we want to put Richard on a prophylactic regimen, and give him an abortive to help ease the acute attack. We decide to use prednisone, one 20-mg tablet in the morning and another with dinner (40 mg/day) for 4 days. We will reduce this to 20 mg/day after the first 4 days, and then to 10 mg/day after another 6 days. We will then taper off the prednisone entirely over the next 4 to 6 days.

Limiting the amount of corticosteroids is important for two reasons: 1) serious side effects are decreased, and 2) if necessary, we may want to utilize additional prednisone later in the cluster series. If the patient has been on a high-dose of steroids for 3 weeks, we cannot use more corticosteroid. In contrast, by keeping the amount to a minimum, we are able to use steroids later in the cluster period. Cluster sufferers may be more prone to femoral head necrosis with the use of corticosteroids.

With the prednisone, we begin a slow release form of verapamil. This is started at 240 mg/day; we may eventually increase to 2 doses per day, which is generally the maximum (480 mg/day). As the prednisone dose is decreased, and the patient is weaned off the medication, it is hoped that the verapamil will have taken effect.

The use of oxygen as an abortive is discussed with Richard, but he prefers to wait. We give him sumatriptan tablets, 100 mg, as he is reluctant to self-inject sumatriptan. Richard is also instructed to apply ice to the areas of pain. (See Table 2 for list of the most common preventative agents prescribed for cluster headaches.)

Results

Six days later, Richard calls the office. He has had 5 very good days, but as the prednisone is being decreased, the headaches are becoming more severe. Sumatriptan tablets do not help; last night, he had 90 minutes of extremely intense pain. At this point, we convince Richard to try oxygen, at 12 to 15 L/min, as needed, and he rents a tank. Richard also is given sumatriptan injections, 4 mg.

We continue the original plan of decreasing prednisone, and we increase the dose of verapamil to 480 mg/d. We will monitor Richard’s blood pressure. He now has oxygen and sumatriptan injections available as abortive agents; adding lithium or valproate are considerations, as is indomethacin.

I see Richard 4 days later. He is now in his third week of clusters, and by his previous pattern, has 1 to 2 weeks left in the cycle. However, at times a cluster period may exceed the previous one in length, and extended cluster periods of up to several months do occur. Richard states that the oxygen does help his headaches.

The clusters are less severe, but still occur regularly twice at night. Sumatriptan injections stop the attacks within 10 minutes of administration. The verapamil may be having some effect as well. He is down to 20 mg/day of prednisone, and we decide to taper off the dose over the next 4 days. If the headaches increase dramatically, he could return to the prednisone.

Six days later, the headaches are gone, and after a week without headaches, Richard is tapered off the verapamil over the course of 6 days. If the headaches were to return during those 6 days, we would immediately increase the dose of verapamil to the maximum of 480 mg, and consider using prednisone again.

Discussion

It is important to chart which medications are most effective for treating a patient’s cluster headaches, so as to be ready to use them for the next cluster series. I usually write the plan for the next series in the patient’s chart, and inform the patient of the plan.

In Richard’s case, we would use oxygen as an abortive, with injections of sumatriptan. As a preventive, he would be given verapamil, increasing to 480 mg/day, and approximately 2 weeks of prednisone. Instead of the injections, zolmitriptan(Zomig) nasal spray would be a consideration, and occipital nerve blocks are a reasonable possibility. SPG blocks are a strong consideration. Other preventives would include lithium, indomethacin, sodium valproate or topiramate.

Most patients with cluster headaches are prescribed both preventative and abortive therapies. Compared to migraine management, we have relatively few medications that are effective for the treatment of cluster headaches. In order to minimize the use of corticosteroids, it is important to initiate preventive medications early in the cluster cycle. For the typical episodic cluster cycle, we begin medication with the onset of the cluster, and discontinue all medication shortly after the cycle ends. There is no demonstrated utility in continuing medication after the episodic cycle ends.  NOTE: This is an updated version of a section from L.Robbins’s book, Advanced Headache Therapy. This discussion is not prescriptive; all medications have side effects, and should not be used without informed consent and a discussion between the patient and physician.

Table 1. Typical Characteristics of Patients with Cluster Headaches

  • Begins between ages 20 and 45, approximately 0.4% of the population
  • Male predominance in a 2.5 to 1 ratio
  • Same time of year with no headache in between the cluster cycles
  • Primarily nocturnal attacks (but may be anytime)
  • During cluster cycle, alcohol triggers the headaches
  • Severe, excruciating, unilateral pain—usually periorbital
  • Ipsilateral rhinorrhea, lacrimation, conjunctival hyperemia, sweating of the forehead, Homer’s syndrome

Table 2. Common Preventive Medications for Cluster Headaches

NOTE: Emgality, a monoclonal antibody used for migraine prevention, is now approved for the use of episodic cluster headache. The migraine dose is 120mg per month; the dose for clusters is 300mg once per month.

Class/Agent Dosage Side Effects Comments
Corticosteroid:

Prednisone

20 to 40 mg/d for 3 to 6 days, then taper off over 4 to 8 days. Corticosteroids have many adverse effects. When used for short periods of time, the most common side effects are insomnia, gastrointestinal (GI) upset, and anxiety. Serious adverse events have occurred with even short courses of corticosteroids. Very effective for cluster headache, cortisone is used primarily for episodic cluster headaches. It is given for 1 to 2 week duration during the peak of the cluster series. Additional cortisone may be given later in the cycle, when the cluster headaches increase. Higher doses may be needed when the cluster cycle is peaking in intensity. Due to adverse side effects, it is very important to minimize the use of cortisone.
Calcium Channel Blockers:

Verapamil ER

At onset of headache, 240 mg/d or bid—maximum dose 480 mg/d Constipation. Electrocardiogram (ECG) should be performed because of possible cardiac abnormalities when higher doses are used. Very effective in episodic and chronic cluster headaches. Often initiated at the onset of the headache, in conjunction with cortisone. Verapamil is then continued while the cortisone is tapered and then stopped. Because of its efficacy and minimal side effects, verapamil is a mainstay of cluster headache prevention.
Lithium 300 mg/d to 900 mg/d Well-tolerated at low doses; drowsiness, mood swings, nausea, tremor and diarrhea may occur. Helpful for chronic cluster, and to a lesser degree, episodic cluster headaches. It may be combined with verapamil and/or cortisone. Blood tests need to be performed to assess kidney and thyroid function
Non-steroidal Anti-inflammatory Agents (NSAIDS):

Indomethacin

Indomethacin: 25 mg once or bid; up to 75 mg bid or tid. GI side effects may limit use. Powerful NSAID, indomethacin can be helpful for some cluster headache patients.
Anti-Epileptic Agents:

Sodium Valproate

500 mg/d to 1500 mg/d

 

May cause weight gain, fatigue, and GI upset, among other side effects. Valproate and topiramate are occasionally effective against cluster headaches. They are the mainstay of treatment against migraines, but less effective against cluster headaches.
    Topiramate 50 mg/d to 200 mg/d Does not cause weight gain, but cognitive side effects may limit use.
Botulinum Toxin A Injection(only occasionally used)(off label for cluster headache; not as effective as for chronic migraine) 50 to 200 units Safe, usually no adverse effects; may cause eye droop, or (rarely) generalized weakness. Botulinum toxin type A FDA-approved for chronic migraine. While the injections are not as effective for cluster headaches, they do help in some patients.
Occipital Injection:

Corticosteroid

Triamcinolone: 20 to 40 mg

Other forms of injectable steroid have also been utilized.

Steroid injection: local site reaction, or systemic corticosteroid effects (see above). May decrease cluster headache occurrence for up to 4 weeks.
    Bupivacaine Bupivacaine: 2 to 5 mL) Bupivacaine: allergic reactions may occur (rare) May decrease cluster headache occurrence for up to 4 weeks.

Sphenopalatine Ganglion(unilateral on the side of the cluster)

Nerve Blocks(SPG Blocks)      Bupivicaine 0.5%   Bupivicaine              Serial(2 to 4X per week)

allergic rxn(rare)      blocks may be effective

Tx360 device  or SphenoCath(these are expensive); Or, the patient may do it at home, (VERY INEXPENSIVE) with a TB syringe and atomizer, with 4% lidocaine. We usually demonstrate it in the clinic for the first time. A plastic spray bottle, with lidocaine, may also be utilized.

 

* Lawrence Robbins is a headache specialist and neurologist north of Chicago. He is an assistant professor of neurology, CMS. Lrobb98@icloud.com

President’s Column: Living with Chronic Pain During the COVID-19 Pandemic

Ann Quinlan-Colwell, PhD, RNBC, DAAPM

During the last five years, the focus upon, and priority for effective management of pain have dramatically shifted.  After more than a decade of efforts to improve the awareness of pain and appreciate the need for pain management, health care system administrators and providers were keenly aware that pain management was an important health care need.  In addition, in 2013 they learned that the patient experience of care constituted 30% of the weight of value based purchasing (CMS, 2013).  At the same time, they realized that patient satisfaction with pain management was an important component of the general patient experience of care.  They also realized that patient satisfaction with pain management was an important component of the patient experience.  Pain was a strong focus of health care system administrators, clinicians.  Then in 2016, the opioid crisis emerged and served as a potent change agent.  The focus and attention of heath care system administrators and clinicians shifted from concern about patient satisfaction with pain to preventing opioid misuse and abuse.  It is not possible to know to what degree, on a visceral level the opioid crisis touched clinicians who had been taught to submerge their ophiophobic fears.  They now could quote support for not prescribing opioids or at least not as many opioids.  Although I have not done a literature comparison, it certainly seemed as time passed information about opioids and substance use disorder far supplanted information about pain in the literature during the last few years.  Then in 2019, two icons of pain management ceased to exist.  The loss of the American Pain Society and the Academy of Integrative Pain Management as sources of leadership, guidance and research were significant.  As we entered 2020, I was hopeful that we had suffered the worst blows to pain management.  Yet new challenges face us.

In January 2020, the 2019 novel coronavirus (COVD- 19) was reported in Lancet.  On the surface many may wonder what negative impact COVID-19 could have on people living with pain. Unfortunately, during this time the barriers that people living with pain face are bolstered and in some cases expanded.  Many people living with chronic pain have serious co-morbidities venturing outside their home is not recommended (Szalavitz, 2020). It is difficult to maintain a safe distance of 3 to 6 feet in community settings or stores.  As an example, last week, I was standing 6 feet behind a man in a supermarket who was 6 feet behind the person in front of him.  A late middle aged woman started to stand in front of me.  I explained that I was in line and maintaining safe space and social distancing.  She waved her hand and said “Whatever!”  She then proceeded not to respect space behind me.  She didn’t seem to understand or accept the concept of personal space and social distancing. Currently when it is necessary for people who live with pain to go outside for a clinician visit or to refill a prescription transportation options may be more limited, less safe or unavailable.  Some may feel they need to choose whether to comply with quarantines and go without pain medicine or break the quarantines to obtain the medicine (Szalavitz, 2020).

Last week, the following important information regarding opioid prescriptions during the COVID-19 pandemic was written by members of the Practical Pain Management Editorial Board (PPMEB, 2020): “with federal law superseding state law, and with the current coronavirus declared as a public health emergency, providers are in fact able to prescribe controlled substances, such as opioids, via telemedicine. The DEA’s Diversion Control Division has noted that, “For as long as the Secretary’s designation of a public emergency remains in effect, DEA-registered practitioners may issue prescriptions for controlled substances to patients for whom they have not conducted an in-person medical evaluation, provided the following conditions are met: The prescription is issued for a legitimate medical purpose by a practitioner acting in the usual course of his/her professional practice; The telemedicine communication is conducted using an audio-visual, real-time, two-way interactive communication system; and The practitioner is acting in accordance with applicable Federal and State laws.”   Additional information is available at www.deadiversion.usdoj.gov/coronavirus.html.

Other limitations are facing people living with pain who are trying to access integrative therapies which help them to manage pain. Physical therapy, massage, chiropractic, yoga, tai chi, water aerobics, swimming and fitness centers are not currently accessible in many communities.  Again, technology can be of help for some.  There are apps on smart phones and tablets that guide yoga and tai chi.  There are dance and exercise videos available as well. Certain out-patient physical therapy groups are guiding family members and patients via teleconferencing while some nurses are working with patients with relaxation techniques over the telephone or via teleconferencing.  For most people, living during this COVID 19 pandemic is a stressful time that can lead to sleep difficulty, anxiety and depression. For people living with pain, each of those can  make the perception of pain more intense and/or can make it more difficult to manage.  Similar to yoga and tai chi, there are many apps on electronic devices to facilitate relaxation and promote sleep.  Psychological oriented hot lines are available to support people with anxiety or depression.  Some clinicians are modifying their work to a teleconferencing mode. Recently the Centers for Medicare and Medicaid Services (CMS) expanded access to and coverage for telehealth care including virtual check-in and e-visits provided by clinicians including physicians, nurse practitioners, and licensed clinical psychologists (Drakulich, 2020).

CMS.gov table available at https://www.practicalpainmanagement.com/sites/default/files/imagecache/lightbox-large/images/2020/03/26/03.17.2020%20Summary%20of%20Medicare%20Telemedicine%20Services%20Chart.png

Continuing patient education is imperative for clinicians and for people living with pain to learn about the new modifications for opioid prescribing and the expanded telehealth options.  It is also important for them to learn that there are a number of scams alleging to be from Medicare and Social Security.  People living with pain may be vulnerable to these and need to know to be cautious.  One patient with a long history of mental health issues, responded to a spam and unwittingly surrendered her Medicare coverage and agreed to a very pricey private insurance that did not meet her needs.  Fortunately, a strong patient advocate was able to intervene and reverse the agreement.

There is no doubt that during 2020 patients living with pain will be challenged with stress and barriers.  As professionals there are ways that we can be supportive and helpful.  We may even find that by meeting the challenges of COVID-19 we will learn new options for helping and caring for people living with pain.  We may even find that they may be more effective.

References:

Centers for Medicare & Medicaid Services. (CMS).  (2013). Hospital Value-Based Purchasing. Available at http://www.qualitynet.org/dcs/ContentServer?cid=1228772237147&pagename=QnetPublic%2FPage%2FQnetTier3&c=Page.  Accessed 3/30/2020.

Drakulich, A. (2020).  Telemedicine in the Time of Coronavirus.  March 16, 2020.  Practical Pain Management.

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., … & Cheng, Z. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet395(10223), 497-506.

Practical Pain Management Editorial Board. (PPMEB).   (2020).  Managing pain and related symptoms during coronavirus.  March 16, 2020.  Practical Pain Management.

Stephen, P. (2016). Study – Wilmington No. 1 in opioid abuse.  Star News.  https://www.starnewsonline.com/article/NC/20160421/NEWS/605049449/WM. Accessed 3/30/2020.

Szalavitz, M.  (2020). People who take opioid painkillers are getting skrewed thanks to coronavirus.  https://www.vice.com/en_us/article/z3b5nj/coronavirus-shows-just-how-cruel-our-drug-laws-are-for-pain-patients-and-methadone-users   Accessed: 3/30/2020.

COVID-19 and the SPS Annual Meeting

Lori H. Postal, RN, MHA

As COVID-19 continues to influence individual and corporate function worldwide, The Southern Pain Society leadership is working diligently to ensure the best plan for our upcoming Annual Meeting in September. We would like all to know that while information on the current unprecedented pandemic is evolving quickly, your health and safety remains our primary concern.  The SPS board is meeting virtually and regularly and is currently hopeful that the meeting can be held as scheduled and that you will attend. However, we are also preparing a variety of contingencies in the event that a change should be necessary.

As COVID-19 evolves and more information becomes available, we will keep you informed of updates and any further decisions through our website, social media platforms and emails.

Thank you for your membership, support and engagement as we work through this crisis.  Please take care of yourselves and your loved ones and especially those on the front-line caring for patients.

Determination of Adverse Effects In Clinical Trials

Lawrence Robbins,M.D.

The efficacy of new drugs is usually reasonably accurate. We have multiple scales for efficacy, and the studies are powered for clinical effect. However, the studies often produce inaccurate adverse event or adverse effect profiles. To determine the likely adverse effects, post-approval we have to piece together multiple lines of evidence. These include published studies, physician experience, the FDA/FAERS site reports, and patient experiences. The physician online chat boards have been very helpful in outlining common adverse effects. The moderated and controlled Facebook patient chat boards have also been somewhat useful. I have previously published on the adverse effects of the migraine monoclonal antibodies. We(myself and Brooke Phenicie,NP-C) recently published a “checklist of adverse effects” study involving the migraine monoclonal antibodies. (1,2,3). I report a brief summary of those results here.

Recap of Results and the Utility of a Checklist

Initially patients were asked about adverse effects, and then they were presented with a checklist. 79 of the 119 patients identified at least one additional adverse effect by use of a checklist. Many patients described multiple additional adverse effects. The majority of additional adverse effects were mild. This study demonstrates the value of a checklist of symptoms in the evaluation of adverse effects.

Monoclonal Antibodies for Migraine Prevention: The Acquisition of Adverse Effects

As of September 30, 2019, the U.S. Food and Drug Administration (FDA) Adverse Events Reporting System Dashboard lists 20,871 adverse events attributable to the 3 migraine monoclonal antibodies. 2,825 events were deemed serious, with some identified as life threatening. (4) Only a small proportion of actual adverse events are reported to the FDA. For only 1.3 years of use, these numbers are staggering. The FDA, as well as similar organizations in other countries, would do well to investigate these adverse events. Adverse events attributable to erenumab accounted for 16,215 (2,367 serious) of the total. Galcanezumab use resulted in 3,465 (284 serious) adverse events, while fremanezumab had 1,191 (178 serious) reports. (4) Erenumab was the initial mAb prescribed in the U.S., and is still the mAb most commonly utilized. This may be a primary reason for some of the discrepancy between erenumab and the other mAbs with regard to the number of reported adverse events. Over time we will be able to determine if one mAb truly carries an enhanced risk for adverse effects. These mAb numbers are significantly higher than those reported for onabotulinumtoxinA. OnabotulinumtoxinA only averages approximately 2,000 reports per year, with few serious issues (in the doses used for headache).
We have prescribed mAbs to over 1,200 patients and they have reported a multitude of adverse effects. Constipation (20% of patients in our study on erenumab, less among the other mAbs) is the most commonly reported AE. (5) At times the constipation is severe, greatly affecting quality of life. Other adverse effects across all 3 mAbs have included: worsening headache (6%), depression (4%), fatigue (4%), nausea (4%), joint pain (3%), and hair thinning or loss (3%). (2) We have encountered a serious adverse effect in 4 patients, including: 1. A 60-year-old woman who had an episode of reversible cerebral vasoconstriction syndrome, which resolved, 2. A 21-year-old woman with a history of hemiplegic migraine (none since 2015), on the birth control pill, who suffered a probable migraine-related stroke, with an 80% improvement over 5 months, 3. A 65-year-old woman, with a history of rheumatoid arthritis, who reported severe joint pains and fatigue, which resolved, and 4. A 31-year-old woman who suffered from severe neurologic symptoms, including hemiparesis. She also suffered from joint pain and fatigue. A complete work-up was negative, and she eventually fully recovered.
We have been in communication with many headache providers concerning their experience with the CGRP mAbs. Constipation is commonly described as an AE. The rate of constipation that these providers report varies between 10% and 80% of patients. Anecdotally, it appears that erenumab causes constipation at an increased rate over the other mAbs. One observational study concluded that adverse effects accounted for 33% of discontinuations from erenumab. (6) Most providers feel that the AEs in clinical practice outnumber those reported in the studies. There also are providers who have encountered very few adverse effects among their patients.

The CGRP monoclonal injections (primarily erenumab) were reviewed by Quarterwatch, a publication that evaluates new medications. They rely upon a number of sources, including post-approval studies and the FDA reports. Quarterwatch researchers cited the “sheer number of case reports.” They noted that a large number of patients had experienced adverse events. Constipation was the most prominent AE. Hair loss was also mentioned as generating a clear signal. (7)

Other AEs acknowledged by Quarterwatch included muscle cramps, muscle spasms, and arthralgias. Thirty-five cases of anaphylactic shock were recognized. Depression was also listed as a concern. They state that “depression warrants additional study.” The authors mentioned signals for cardiac events. These included arrhythmias, palpitations, tachycardia, and cardiac arrest. Cases of loss of consciousness were also described. (7)

Quarterwatch concludes that “….it is likely that adverse effects of this migraine preventive were underestimated in the clinical trials.” In addition, they state “…the long-term effects of blocking all the functions of a highly prevalent signaling molecule remain undetermined.”
Quarterwatch, in December 2019, reviewed the frequency with which adverse events are reported to the FDA. Quarterwatch estimates that, in general, only 1% of serious adverse effects are actually reported to the FDA. Side effects to generics are rarely reported. However, the newer branded biologics, such as the migraine mAbs, are reported more often. Still, there are many serious side effects to the mAbs that go unreported.

The patient online chat boards and support groups help to provide insight into “real world” experience. Many patients state that they have had excellent results, with no adverse effects. However, many adverse events are also described. I have reviewed 400 adverse effects that were felt to be credible. The most common AEs described online by patients include fatigue, constipation, hair loss, depression, anxiety, and nausea. Many patients attempt to discuss adverse effect with their physician, and often they are dismissed with phrases such as “That AE cannot be due to the drug. They are safe.”
The adverse effects that we gleaned from patient comments somewhat matches the AE profile reported in our previous studies. They are also similar to what is stated on the FDA Adverse Event Reporting Dashboard.

Interfering with the molecule CGRP carries a multitude of possible risks. Evolution has decided that CGRP is a vital compound throughout the body. CGRP plays an important role during stress. These compounds have not been studied under stressful conditions. The blood brain barrier does not protect certain key areas, such as portions of the hypothalamus and pituitary glands. (3) Studies of various hormones, particularly in younger patients, have not been published.

The Phase 2 and 3 mAb studies significantly underreported the adverse effects. There are a number of reasons as to why they missed the adverse effects. Thomas J. Moore (Senior scientist, Institute for Safe Medication Practices) outlined this in his chapter “Assessment and Reporting of Harm.” (8) There are myriad scales and methods for describing efficacy in trials. With regard to adverse events or effects the methods for evaluation are lacking. Trial subjects are usually healthier, with fewer psychiatric and medical issues, than the patients we encounter in our offices. As compared to our chronic migraineurs, most of the study patients have used fewer preventive medications. For most of the mAb studies patients were simply asked, during follow-up visits, if they had any new symptoms or issues. This method may identify many of the serious AEs, but usually underreports milder issues. Psychiatric AEs often are not volunteered by the patient. Study personnel ideally should have a checklist of likely side effects. Patients should be asked, during each visit, about the predetermined items on the list. Adverse effects differ regarding duration of effect, severity of the AE, and how often it has recurred. It would be best if each adverse effect would be categorized as “mild, moderate, or severe.” The length of time that the AE remains is also important. (8) For instance, there is a major difference between the patient suffering from mild constipation for three days versus a person who suffers two months of severe constipation. The adverse event classification systems include the National Cancer Institute Common Terminology Criteria for Adverse Events, and the Medical Dictionary for Regulatory Activities (MedDRA).
The disaggregating of adverse effects leads to underestimating certain AEs. For example, fatigue may have a several synonyms, such as malaise or tiredness. “Fatigue” for one person is different from “fatigue” for the next person. (8) After completion of the study it is theoretically possible to re-aggregate these symptoms. However, re-aggregation is not accurate. Future trials should carefully define each probable adverse effect.

The studies are underpowered with regard to identifying AEs. Assuming the incidence of one particular AE is one in 1,000 patients, the study needs 3,000 patients in order to uncover one case, with 95% probability. If we want to uncover 3 cases, the study would require 6,500 patients. (9) The numbers in the monoclonal studies were inadequate. The studies also do not extend long enough to adequately assess adverse effects.

Going forward, studies should use a checklist of symptoms. In addition, carefully defining each possible adverse effect would help to avoid “disaggregation” of symptoms. We need to have a more accurate picture of adverse effects coming out of the studies.

References

1. Robbins L., Phenicie B. CGRP Monoclonal Antibodies for Chronic Migraine Prevention: Evaluation of Adverse Effects Using a Checklist. Practicalpain management.com. March-April 2020.
2. Robbins L. CGRP monoclonal antibodies for chronic migraine: year 1 of clinical use. Practical Pain Management. 2019; 19(6):58-62.
3. Robbins L. CGRP antagonists: physiologic effects and serious side effects. Headache. 2018;58(9):1469-1471
4. FDA FAERS Website: https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis
5. Robbins L. CGRP monoclonal antibodies for chronic migraine. Practical Pain Management. 2019;19(2):45-52.
6. Robblee JV, Mendez N, Potter J, Slonaker J, Grimsrud KW, Starling AJ. Post-market observational study of patient experience with erenumab. In: Headache. 2019;59(supp 1):48.
7. A New Class of Drug for Migraine Prevention. In: Quarterwatch(a publication of The Institute for Safe Medication Practices)Aug. 2019; Available at: www.ismp.org/quarterwatch
8. Moore T, Assessment and reporting of harm. In: Fundamentals of Clinical Trials, fifth edition, by Friedman L, et al. Springer, 2015. Chapter 12,255-274.
9. Furberg BD, Furberg CD. Evaluating Clinical Research. All that Glitters is Not Gold (2nd edition). New York, NY: Springer, 2007, pp.17-18 10. Ashina M, Goadsby PJ, Reuter U, et al. Sustained efficacy and long-term safety of erenumab in patients with episodic migraine: 4+-year results of a 5-year, open-label treatment period. Presented at: 61st Annual Scientific Meeting of the American Headache Society; July 11-14, 2019; Philadelphia, PA. Oral IOR10.

People Who Take Opioid Painkillers Are Getting Screwed Thanks to Coronavirus

Quarantined people have to go out to get their prescriptions and can’t get a backup supply.
by Maia Szalavitz

Mar 24 2020, 6:00am

https://www.vice.com/en_us/article/z3b5nj/coronavirus-shows-just-how-cruel-our-drug-laws-are-for-pain-patients-and-methadone-users

SPS Treasurer Transition

As you may know or have read in our President’s Column, Dr. John Satterthwaite has stepped down from his long-standing role as SPS Treasurer and will remain on the board as a non-voting member. We are grateful for his 34 years at the financial helm of the organization and appreciate his wisdom, historical perspective and recommendations that have kept SPS healthy, financially sound and robust.

As such, we are pleased to announce the appointment of Randy Roig, MD as the Southern Pain Society’s new Treasurer. Dr. Roig has been on the SPS board as at-large director for the past year. Due to his extensive finance and non-profit experience, coupled with his leadership interest in our organization, Dr. Roig has stepped into his new role effective January 1, 2020. We are delighted to have his expertise. Dr. Roig will be on the 2020 SPS ballot as a nominee for formal election.
Dr. Randy Roig is a resident of New Orleans and is a summa cum laude graduate of the Tulane School of Engineering and the LSU School of Medicine in New Orleans. He completed his physical medicine and rehabilitation (PM&R) residency in 1996, serving as chief resident. He is holds American Board of Medical Specialties (ABMS) certifications in PM&R, spinal cord injury medicine, and pain medicine. He is presently practicing at the Southeast Louisiana Veterans Health Care System, where he is the Associate Chief of Staff for Education and Designated Education Officer, Assistant Chief of the PM&R Service, and Chief of the Pain Medicine Section. He is on the faculty of both LSU in New Orleans and Tulane University, as well as Emory University in Atlanta, Georgia. He serves as the program director for the pain medicine fellowship training program and clinician co-director of the course in musculoskeletal medicine and dermatology at LSU. He is volunteer Executive Editor of Rehab in Review, a monthly journal for the field of physiatry published by Emory University.

Dr. Roig has served on numerous nonprofit boards and committees within the medical community, including the Association of American Medical Colleges and the American Academy of Physical Medicine and Rehabilitation (AAPM&R). He also serves as co-chair of the Medical/Legal Interprofessional Committee of the Louisiana State Medical Society (LSMS) and the Louisiana State Bar Association.

Dr. Roig’s new role includes the financial stewardship of SPS and from our by-laws: “The Treasurer will be responsible for the custody of the Society’s funds and securities and for maintaining a full and accurate record of receipts and disbursements. He shall act within the confines of good business practices and under the supervision of the board of directors.”

Welcome!

Update on Gepants: New Abortives for Migraine

Lawrence Robbins,M.D.

Gepants are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists. The preventive CGRP monoclonal antibodies(Aimovig, Emgality, Ajovy) are large molecules, delivered once per month as a SQ injection. Seven gepants have been developed since 2004. (1) Telcagepant was extensively studied, but withdrawn due to hepatotoxicity concerns. CGRP has many effects throughout the body. CGRP triggers a cascade of inflammatory mediators that feed into the trigeminovascular system. By blocking CGRP, the gepants stop the process prior to inflammation.

Regarding migraine, CGRP is an inflammatory compound. They will initially be utilized as migraine abortives, but eventually they will also be used to prevent migraine. The gepants may be helpful for 3 groups of migraineurs. They will be prescribed for a number of patients who found triptans (sumatriptan, rizatriptan, zolmitriptan, etc.) to be ineffective. In addition, gepants will be used for certain patients who cannot tolerate triptans. Finally, for those patients with significant cardiac or cerebrovascular risk factors, the gepants may be relatively safe, since they do not constrict cardiac or cranial arteries. While efficacy is modest, these are well tolerated medications.

The first gepant to come to market will be ubrogepant. Almost 2,700 patients participated in the ubrogepant ACHIEVE studies. (2,3) The doses have ranged from 25mg to 100mg. The t-max is 0.7 to 1.5 hours. Approximately 20% of patients who used the 50mg dose were pain free after 2 hours. While 25mg and 100mg tablets of ubrogepant were evaluated, it is likely that 50mg will be the primary dose. Ubrogepant was well tolerated, with 2% to 5% of patients reporting nausea, somnolence, dry mouth, dizziness, or upper respiratory tract infections. No serious adverse events were reported. The safety and tolerability were also explored in a 52 week extension study. Few adverse events, and no hepatotoxicity was reported. The effect of ubrogepant on the patient’s most bothersome migraine symptom was evaluated 2 hours post-dose. 39% of those treated with ubrogepant reported that their worst migraine symptom was resolved. The therapeutic gain for ubrogegepant (active drug vs. placebo) is relatively low, 6.4%-9.4%. In comparison, the therapeutic gain for sumatriptan is 16%-21%.

Rimegepant is another gepant, in development for abortive and preventive use. The dose is 75mg, with a t-max of 2 hours. In the 2 main trials, 19.4% of patients achieved pain freedom at 2 hours. (4) 37% of patients reported freedom from their most bothersome symptom. As with ubrogepant, no significant liver toxicity was reported. Adverse events were low, with nausea being reported by 1.4% of patients. The therapeutic gain for rimegepant is 5% to 7.6%.

A third gepant, atogepant, is currently being studied.

The gepants will be a useful alternative to triptans. Many patients find triptans to be ineffective. Some migraineurs cannot tolerate the adverse effects of the triptans. For certain patients with cardiovascular risk factors, triptans may not be completely safe. Gepants will be considered in these clinical settings. The initial (2 hour) efficacy rates are fairly low, but it appears that gepants may become more effective over 2 to 8 hours. During the trials, these were fairly well tolerated medications. It will take at least several years before we are able to accurately assess the true adverse effect profile of the gepants.

References

1. Olesen J, Diener H-C, Husstedt IW et al Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. 2004. N Eng J Med 350:1104-1110.

2. Allergan Announces Positive Top Line Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at http://www.allergan.com/news/news/thomson-reuters/allergan-announces-positive-phase-3-resul.

3. Allergan Announces Second Positive Phase 3 Clinical Trial for Ubrogepant- an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine. Available at http://www.allergan.com/News/News/Thomson-Reuters/Allergan-Announces-Second-Positive-Phase-3-Clinica.

4. Biohaven Announces Successful Achievement of Both Co-Primary regulatory Endpoints in Two Pivotal Phase 3 Trials of Rimegepant an Oral CGRP Receptor Antagonist for the Acute Treatment of Migraine Available at https://biohavenpharma.com/wp-content/uploads/2018/03/CONFIDENTIAL-BIOHAVEN-PRESS-RELEASE-FINAL-v2.pdf.

Reducing Harm from Opioids – Lessons Learned

Lisa Edgerton, PharmD, BCPS, CPP, Olivia Herndon, MA, and Joseph Pino, MD, MHA

Wilmington is a community in southeastern North Carolina known for its beautiful beaches, historic river-walk district, and the largest domestic television and movie production facility outside of California. In April of 2016, this city also became recognized for something else.

In 2016, Castlight Health released a report titled “The Opioid Crisis in America’s Workforce.” The study noted those who abused opioids are more likely to live in the rural south with 22 of the top 25 cities in Southern states. Furthermore, it named Wilmington, NC as the city with the highest abuse rate in the United States. In response, our medical community mobilized and recruited partners from disciplines outside of healthcare to reduce harm from opioids in our region.

Through a “call to action” where more than 100 regional stakeholders and leaders, the Community Partners Coalition (CPC) was born. This CPC aims to improve collaboration and coordination between those who provide care to individuals seeking access to mental health and substance use services by aligning efforts in the region. A primary focus of the CPC was to improve safe medication disposal options in our region by expanding medication take-back events and permanent drop boxes.

The first medication take-back event was held at New Hanover Regional Medical Center (NHRMC) in March 2009. This event was held at one location on our hospital’s main campus in New Hanover county. NHRMC partnered with the Wilmington Sheriffs office and collected 140 pounds of medication at that event. This solo event continued biannually however, dates were chosen based upon availability of volunteer coordinators and coinciding community events. NHRMC continued to host this single site medication take-back event biannually through the Spring of 2017.

Through the support of the CPC, in the Fall of 2017, this event was expanded to 9 locations within 4 counties and collected 3,680 pounds of medication and 29,675 needles or sharps. This biannual medication take-back event has continued to grow now hosting 19 locations spanning 6 counties in our region.

In October 2019, we collected almost 6,000 pounds of medication, 43,000 needles or sharps and 178 medications, valued at $55,000, that were donated to a local clinic serving those without resources for re-dispensing. Expanding our medication take-back event to 19 locations did present some challenges along the way.

To expand our reach, leaders of the takeback event needed to engage in detailed planning and consider logistical challenges. We aligned our event dates to the Drug Enforcement Administrations (DEA) National Prescription Drug Take Back Day. Aligning with the DEA allowed us to plan for future events as these dates are standardized on the last Saturdays in April and October. Alignment also enabled law enforcement to register event locations in their national website. This site is searchable and provides a map of locations nearest to search area. Alignment with the DEA also connected us to our regional State Bureau of Investigation (SBI). This partnership enabled us to receive support including standard boxes used to collect medications at each take-back location. The SBI supplied NHRMC with 250 evidence boxes that were distributed to site leaders at each take-back location.

When planning to staff each of our sites, federal rules indicate that law enforcement must be present at each medication take-back location. When planning for our Fall 2017 expansion, we discovered that our hospital law enforcement officers could staff all NHRMC and affiliate locations. At the Fall 2017 event, we were able to utilize NHRMC police for 5 of the 9 locations. This allowed us to extend our partnership with local sheriff’s offices and expand to additional sites. We continue to collaborate with our regional county sheriff departments who provide an additional 1-2 law enforcement officers for each location.
NHRMC company police have been instrumental in not only staffing these events but also coordinating with regional law enforcement agencies. They collect and store the medication until the “burn day”. This often occurs 2-3 days after the takeback event. Our event has become so large that NHRMC law enforcement transports over 100 boxes of medication. As a result of our success, we have outgrown the transport capacity of our standard vehicles. We now either have to rent commercial trucks or borrow large box trucks from another department in our hospital.

In addition to organizing law enforcement to be present at each site, we decided we would accept needles or sharps at each of the 19 drop off locations. This became an issue for sites that were not affiliated with a health system because they did not have sharps containers at their locations. Prior to each event, NHRMC now donates sharps containers to each of these sites. Following the event, we now also coordinate with either law enforcement or a volunteer at the site to collect the sharps bins.

To raise awareness of this multi-county, multi-site drug takeback event, we approached our hospital’s marketing department to help us by advertising this event. They created a universal flyer listing each drop off location by county. This flyer is printed in a variety of sizes and is posted across our health system and to each of our drop-off location partners. We also advertise in advance of this event on social media, radio stations and local newspapers as well as media outlets on the day of the event. We also created a NHRMC webpage dedicated to medication disposal where we post our upcoming flyer and list locations of all area permanent drop boxes. Through this effort, we also learned that funeral homes, hospice care centers, veterinarian offices and churches are effective locations to advertise these events and added these sites to our marketing locations for future events. We also realized that we needed to create a Spanish-version of our flyer to appeal to other segments of our community and plan to do so for our next event.

We also discovered that we needed to develop a standard process to enable us to repurpose unused medication. Medication take-back locations staffed with NHRMC volunteers may collect any unused medications and can donate them to a charitable clinic. These medications must meet North Carolina repository rules and regulations to qualify for donation. Following the event, each unused medication collected is visually inspected by a pharmacist to ensure it meets all applicable federal guidelines for donated medications. By following this process, we could donate $ 55,000 of medication to one of our local, charitable clinics.

During our medication take-back expansion in 2017, NHRMC also installed three permanent medication drop boxes across several sites within our health system. Medication drop boxes were installed on the main campus within our Outpatient Pharmacy, at our free-standing emergency department located off campus, and at our critical access hospital located in a neighboring county. It was anticipated that the drop boxes would need to be emptied once a month. When first installed, the permanent drop box in our main hospital, which holds roughly 55 pounds of medication, needed to be emptied every 9-10 days. This was not anticipated. We now collect 1,600 pounds of medication in our 3 permanent medication boxes annually.

Like other communities across the country, Wilmington and our surrounding area have been significantly impacted by the opioid crisis. Through the development of the CPC and the leadership of NHRMC, we expanded our drug takeback events to multiple sites in multiple counties in our region. As a consequence of our success, we also discovered we needed to coordinate law enforcement at each location, establish safe storage, rent large trucks to transport thousands of pounds of medication collected at each event, develop a process to reclaim medication and manage high volume disposal of medication in permanently installed drop boxes across our health system. We are fortunate to have such an engaged community to collectively work to reduce harm from medication. Hopefully, these lessons learned will help you do the same.

Thank You, John Satterthwaite!

Ann Quinlan-Colwell, PhD, APN

Developing this president column is no small task. It is written to pay tribute to our friend and mentor Dr. John Satterthwaite who recently stepped down from serving as the treasurer of the Southern Pain Society during the last 34 years.  John nurtured and guided SPS while significantly impacting many SPS members in ways that can never be repaid. As Dr. Mordi Potash said so well: “it is an absolute truism that there would not be a Southern Pain Society in existence in 2020 if not for John Satterthwaite.” This was echoed by Lori Postal who recently wrote John Satterthwaite has served the Southern Pain Society as a “trusted mentor, historian, voice of reason and steward of our finances.” Not only is John a man of many talents who has contributed greatly to the world of pain management but he has paradoxical qualities as well.  Although he is often a wise sage when on the stage, he is equally comfortable and meaningful being the guide on the side.  He is often a man of few words yet a great storyteller. John has always reminded Dr. Geralyn Datz of “a firm but fair patriarch, if you are under his wing, he is protective and compassionate.”  Several people make the analogy of John steering and guiding the SPS ship. Dr. Harry Gould appreciated John’s welcoming spirit and guidance for the “kids in the candy shop” (the SPS Board of Directors) “to get the most with what we had” (financially). John’s devotion and perspective on the history and the mission of SPS have been priceless.  As I recount these observations and impressions I am nodding my head in agreement. John is an expert physician, teacher, patriarch, sage, guide, shepherd, steward, mentor, storyteller,  navigator, voice of reason, friend and so much more.

Dr. Eric Pearson particularly loves John’s “wisdom and amazing dry sense of humor” which was reflected in preparing for this column.  After sending John some questions about his life, he sent me the “answers to the essay test.”  He was the son of a Station Manager for Capital Airlines born in Clarksburg, W.V. but moving frequently during his childhood and teens.  He had several early occupational goals including being “a trash collector because you could ride on the outside of the truck,” an Air Force pilot and “several other questionable thoughts.” His focus changed while working summers as an orderly and surgical tech in the OR in Georgia, where the anesthesiologists encouraged him to consider anesthesiology instead of surgery which as a fan of the TV show Ben Casey, he found interesting.  In fact, he initially “thought of going into Thoracic Surgery, but the residency was too long, and “ultimately chose anesthesiology because you work in a climate-controlled area and can wear pajamas all day (ha-ha)… It is immediate treatment response medicine and sleeping patients don’t complain.”

John noted that his  “involvement with pain was accidental.”  After practicing for 2-3 years, a neurosurgeon from Memphis, TN moved to the area and asked John to do epidural steroid injections.  As a result, other ortho and neuro doctors followed with similar request, and he became the first person in Greenville, S.C. to be “practicing pain.” Subsequently other surgeons asked if there were injections that could administered for “patients with an unusual pain with discoloration and extremity swelling.”  John’s interest was sparked in what was then RSD (reflex sympathetic dystrophy) which he began treating.  He was told by a local orthopedist that “we never had RSD in Greenville until you came to town.” 

John joined SPS in March of 1987 which qualified him as a Charter Member.  He clarifies: “at least that is what my certificate says.”  His intertest in RSD led him to  attend his first SPS meeting in 1989 because they had a day long program on “RSD” at the SPS regional section meeting, held in conjunction with APS.  Wearing his historian hat, John wrote: “attendance at the regional meetings tended to be greater than the APS meetings and we were subsequently uninvited to hold our meetings with APS.  The first independent SPS meeting was in 1991 in Chattanooga, TN.  I have been to each meeting since then except one.” 

“In 1989, the President of SPS Dan Hamaty, whom I knew because of his involvement with Pain Therapy Centers (PTC), asked me to become Treasurer which I accepted.”  Because of the involve tax and registration paperwork necessary to transfer the office, John continued to act in that capacity until 12/31/2019.  “If not for my current health issues, I would continue as I get to interact with some of the giants in the field and it is fun. I was asked to run for SPS President by Renee Rosomoff 1996, but declined because of this” (responsibility to the role of treasurer).

Because of his interest in pain, John developed a relationship with Dr. C. David Tollison who was a Clinical Psychologist specializing in pain.  Dr. Tollison set up a multidisciplinary pain treatment program in hospital system where John was located. This was the start of PTC of which John became Medical Director with Dave as Program Director.  “Due to the financial success of PTC, other hospitals in the region became interested.  We started a program in Charlotte with Dr. Hamaty as Medical Director, and at one time there were several programs in four states.  Unfortunately, with changing reimbursement, these programs ultimately died out.”

John noted that he has “been surrounded by some of the greats in the field of pain, but the person who has had the greatest influence was Dave Tollison.  We have practiced together for 30 years.  We have edited several books and spoken at many events.  One of my prized possessions is a copy of the 3rd edition of our “Practical Pain Management” which was translated into Chinese.  This was the third bestselling pain text behind Bonica and Raj.”  “Others especially Hu and Renee Rosomoff had a tremendous influence on my life in pain management as well.”

John felt fortunate to meet or work with Hu and Renee Rosomoff, Marty Grabois, Bert Ray, Stan Chapman, Peter Staats, Jeannie Koestler, Ben Johnson, Dan Doleys, Todd Sitzmann, and many other leaders and pioneers in the field of pain management during the last 30 years. He has many SPS related reminiscences.  His most “memorable SPS event was at a Board of Directors meeting in Charlotte in 1996.  President Renee Rosomoff was notorious for micromanaging and long meetings, but this one started at 11:00 am and was finally over at about 1:30 the next morning when someone (not one of us although I wish it had been) set off the fire alarm at the hotel.  Although we were still not finished, nobody went back to the meeting room following the “all clear”.  Even Renee’s husband Hu, who came to all Board meetings because of his love for the organization, had left much earlier.  (FYI, Hu Rosomoff was founding President of SPS, and subsequently served as APS President, AAPM President, and was a giant in the field of pain.  I was privileged to call him a friend.)”  Another favorite memory was that Hu and Renee “attended every Annual Meeting together.  They sat on the front row, in front of the speaker, so you knew they were listening.  After every speaker Hu would stand and provide commentary.  All of it useful, but sometimes critical.  I presented a talk on “Epidural and other steroid injections” at one of our meetings.  I knew Hu was a multidisciplinary treatment advocate.  Despite his being a neurosurgeon, he was very critical of procedures or medications for pain treatment.  His clinic in Miami was one of the leading multidisciplinary pain treatment facilities in the world.  When he stood up, I held my breath until he said my presentation was the most objective and comprehensive discussion on injections he had ever heard.  Quite a relief.”

A memory lane of pain management for John reflects significant change.  It also reflects the “honesty, genuineness, firm opinions rooted in his experience and desire for others to succeed” that Dr. Geralyn Datz described. He relays that today “it has become almost impossible to treat patients appropriately.  In the early years, we treated patients based on our understanding of the pain mechanisms and pathophysiology.  We experimented with injections, infusions, anticonvulsants, antidepressants, calcium channel blockers, anti-inflammatory, and other medications.  This laid the groundwork for much of what we use now or try to.  Now every pharmacist, insurer, lawyer, and government/insurance bean counter are practicing medicine and preventing, or impeding, treatment of patients.  Malpractice suits and regulatory agency threats are constant threats.  Cost effective has become the mantra instead of patient effective.  I agree with evidence-based medicine, but we had no evidence in the early years.  In fact, many of the studies now quoted began with a ‘what if we try this?’  That was our work.  It’s hard to formulate a treatment program with a bureaucrat or insurer standing in the way.  Yes, PT, complementary treatments, behavior modification are excellent alternatives to opioids, but no insurer will cover them.  Private practice is handcuffed by payors.”

When asked about the current opioid abuse/misuse crisis, John replied: “I think back to Russell Portenoy who basically asked, ‘what is the difference in pain from a vertebral fracture from metastatic cancer and from osteoporosis?’  Answer, there is none except the cancer patient will probably die sooner than the osteoporosis patient.  This was the beginning of the use of opioids for non-malignant pain.  Unfortunately, practitioners were unable or unwilling to appropriately screen and evaluate patients and prescribing went out of control.  It has become extremely difficult in this day of volume practice to appropriately evaluate who is a candidate for opioid use and who is not.  Evaluating who is and is not a candidate for chronic opioid use is not easy and is quite time consuming, and you must be able to say no.  Opioids are also being inappropriately prescribed for acute pain.  A postop hernia repair does not need 30 mg of  Oxycontin for pain management.  Back strain does not require initial treatment with opioids when other modalities have not been tried.  It is just quicker and easier to write a script than do a more complete evaluation and get other  treatments declined.  Finally, there are people who misuse or abuse opioids, and many practitioners do not take the time to weed them out.  Unfortunately, there is not a lab test for pain, and a history and physical have become relics of the past while lab studies, computers, and x-ray have taken over.”

If John could wave a magic wand to achieve a program/practice of perfect pain management, he would have two wishes.  “First, patients would be honest and not lie or manipulate, but this will never happen.  Second, there would be complete coverage for interdisciplinary treatment to include behavior modification, psychological evaluation, physical therapy, aquatic and other therapy, medications as indicated, injections as indicated, necessary evaluations and procedures, rehab and work hardening, and last but not least, any opioid prescriptions for longer than two weeks needs to be approved by a specialist. In fact, as many clinics do, no one should be placed on opioid therapy without a psychological evaluation from a qualified pain psychologist and undergo ongoing eval and treatment.”

In conclusion to reflect the wonderful Satterthwaite wisdom that Eric Pearson noted, John offered a few pearls and words of wisdom for pain management clinicians.  He stressed that “the key word is clinician.  Remember you are a professional.  If you are a one trick pony, one trick is all you have.  If the only thing you have is a hammer, you will be useless for anything but a nail.”  “Pain has been defined by the IASP as An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. The proposed new 2019 definition is: An aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury.  In those definitions notice three factors: actual or potential tissue injury, sensory experience, emotional experience.  Each of these aspects needs to be addressed.  Injections, pills, or counselling only deal with one issue.  Pain is a complex issue so there is no simple answer or treatment.  So, stop trying to hammer that bolt through the steel plate with your hammer.”

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