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9 Articles in Volume 8, Issue #1
Spine-related Pain in Sports Medicine
Outpatient Interventional Treatments for Migraines and Pain Flare-ups
Identifying Abusers Prior to Initiating Chronic Opioid Therapy
Urine Drug Tests in a Private Chronic Pain Practice
Platelet Rich Plasma (PRP) Matrix Grafts
Role of Sustained-release Opioids in Treating Chronic Pain
Adenoid Cystic Carcinoma of the Parotid Gland
Evaluation and Management Codes Drive Medical Necessity
Grappling with the Ethics of Practical Pain Management

Outpatient Interventional Treatments for Migraines and Pain Flare-ups

An outpatient clinic can provide an effective variety of IV treatments—individually or in combination— for definitive control of pain.

Headaches/migraines and intractable ongoing pain flareups can be treated in any number of ways by healthcare practitioners. A patient can surely be sent to the ED to have their headache treated, but, we all know this is fraught with multiple frustrations and failures. And, most often, the patient surely doesn’t win. This article attempts to describe more aggressive and definitive treatments available in the outpatient pain and headache clinic setting. In a specialized setting, used by practices that offer intravenous therapy services, intractable pain, headaches and migraine flareups can be successfully treated. Of course, it does require nursing staff trained in IV therapy to start and monitor IV lines. Also, pulse oximetry monitoring can be very desirable in many cases as I will note for some of the medications. A comfortable room or rooms where patients can be treated—hopefully where lights can be dimmed—would also be ideal. Many of my IV rooms are multi-use so that the psychologists or the nurse practitioner may use them as well. We have a room that we use for cervical and lumbar traction and also an EEG room that can be used for IV treatments. These treatment rooms have easy chairs in them.

Our clinic compiled its track record in treating headache and pain patients with refractory problems utilizing IV medication therapy. We presented this data in 1998 at an international pain conference.1 Our initial experience was that in excess of 97% of our treated clinic patients fared exceedingly well as far as their headache and pain symptoms were concerned. Extremely few had to be retreated after they saw us in the clinic (30 out of 1000 patients treated). This suggested that we were not only clinically efficient but, on a cost basis, aggressive clinic treatment of headache was less expensive than treatment in the ED, as well. There are multiple lines of data to suggest that having headaches is an enormous economic burden to the person, their employer, and society.2-17

Migraines/Headaches

A recently published study quantified the direct and total costs of migraines in adults, and in children. This was also done with respect to the presence or absence of comorbidities such as depression and anxiety.3 Adults and children with migraines had increased costs of treatment between 2.4 and 3 times that of cohorts without migraines. Children with migraines and anxiety/depression comorbidities had up to 8.4 times the annual costs for treatment. Another recent study looked at total health care costs in families with migraineurs (pharmacy and medical claims data as well as work absenteeism and short- and long-term disability).4 Total healthcare costs were 70% higher in families with migraine sufferers; even more cost was associated with a child that had migraine compared to an adult. However, when both a parent and a child were affected with migraines, the total costs were $2,500 higher each year and both direct and indirect costs were elevated.

Studies have shown that early treatment with migraine-specific agents like sumatriptan is more effective than if the migraine pain is moderate to severe when treated. In one study, a model designed to assess the costs and outcomes per treated migraine attack,8 early treatment with sumatriptan when migraine pain was mild resulted in substantially decreased total costs per treated attack—with decreased time with headache pain, and an increased proportion of migraineurs pain free at four hours without recurrence. Fewer physician and emergency department visits were noted as well.

A number of US-based studies7,9-11,16,17 speak eloquently to the immense national burden of migraines and other headaches on the worker, the employer and society in general. Studies and surveys performed in other countries (Canada, France, Brazil and multinationally2,5,6,12-15) closely replicate the findings from US-based studies regarding the widespread prevalence of migraines and the need for successful treatment strategies to decrease workplace absenteeism and disability.

Musculoskeletal Disorders

Similar data also exist abundantly for the cost burden of pain disorders in the workforce.18-25 A recent study sampled health care costs (direct and indirect) for employees with painful conditions and compared them to a random sample of employees. The costs among the former group were 1.5-3.5 times higher annually ($7,088-16,874 compared to $4,849).18 An interesting older incidence study looked at nationwide data for various job categories regarding total cost for medical care, lost productivity and pain and suffering.19 At the top of the list for average cost (cost per worker) were: taxicabs, bituminous coal and lignite mining, logging, crushed stone, oil field services, water transportation services, sand and gravel, and trucking. Industries high on the total-cost list were trucking, eating and drinking places, hospitals, grocery stores, nursing homes, motor vehicles, and department stores.

Musculoskeletal disorders, particularly those with a component of chronic pain, impose a significant direct cost burden on health care systems and have even greater indirect losses of productivity. Occupational back pain is the most common and costly musculoskeletal disorder in the workplace.20 Characteristics associated with prolonged disability among cases of work-related back pain include: employment in high-risk jobs that demand heavy lifting, failure to take advantage of job accommodations and granting of disability benefit payments.

Occupational low back pain is widespread in our society. One study attempted to create a model to calculate the net costs to an employer to put in place ergonomic interventions for employees.21 The study showed that putting in interventions could result in lower costs through better productivity. It was felt the employer should play a more active role to prevent back pain. Another study researched total outpatient costs of four common treatments for low-back pain (LBP) at 18-months follow-up. 681 patients were assigned to 1 of 4 treatment groups—medical care only (MD), medical care with physical therapy (MDPt), chiropractic care only (DC), or chiropractic care with physical modalities (DCPm). DC was found to be 52% more expensive than MD (p22

Arthritic Disorders

Arthritic disorders are quite prevalent in the US (16% of the population) and are associated with significant poor quality-of-life issues, particularly in terms of bodily pain and physical functioning, where quality of life is lower than that for gastrointestinal conditions, chronic respiratory diseases, and cardiovascular conditions.23 A study of arthritic disorders in three countries, including the US, documents that these disease states account for up to 1-2.5% of the gross national product of western nations. This burden comprises both the direct costs of treatment and interventions and also indirect costs, such as premature mortality and chronic and short-term disability.

A more recent study examined prevalence of arthritis and arthritis pain exacerbations in US workers including impact on functioning and lost productive work time (LPT). Workers with arthritis pain exacerbation account for a disproportionate share of the arthritis-related LPT cost.24 Participants completed a telephone interview to measure the prevalence of arthritis and pain exacerbations, LPT (in hours and dollars) and functional disability using a WOMAC scale. Pain exacerbation occurred among 38% of participants with arthritis. Workers with pain exacerbations were significantly more likely to have higher WOMAC scores (38.6 versus 29.6; P=0.0041). The estimated annual LPT cost from arthritis in the US was $7.11 billion, with 65.7% of this cost attributed to the 38% of workers with pain exacerbations.

Fibromyalgia

A recent study examined the characteristics and healthcare costs of fibromyalgia syndrome (FMS) patients in clinical practice. The sample consisted of 33,176 FMS patients and an identical number in the comparison group. Mean age was 46 years, and 75% were women. FMS patients were more likely to have various comorbidities, including painful neuropathies (23% vs. 3% for comparison group), anxiety (5% vs. 1%), and depression (12% vs. 3%) (all P

Outpatient IV Treatments

One of the most gratifying experiences in my practice is the ability to intervene directly with a treatment to reduce or eliminate an ongoing pain or headache flareup. Most often, this takes the form of an intravenous infusion of medication(s) in the clinic. I find this much more effective (and very much cheaper) than treatment in a hospital-based or emergency room setting. For a headache and pain practitioner like myself, these IV techniques are indispensable to my day-to day practice and treatment of my patients.

Obviously, one must be set up to do IV treatment in order to offer this technique of acute intervention. This takes less practice preparation than one might think. Some space has to be allocated to performing the service but this is often the same examination room where I see patients. In my case we have a block room, where up to four IV treatment can take place simultaneously, separated by curtains. We also have a common-use room used by the psychologists for sessions and biofeedback, by the physical or massage therapist for treatment and by myself to see patients with their family members. We can muster an IV in the easy chair. Some days, I start my own IVs and the rest of the time the nurse or the NP does the honors. Either way the job gets done. We routinely use pulse oximetry monitoring, as some of the treatments are more safely done with this. We pick up cardiac rhythm disturbances that might otherwise not be known using this simple technique.

There is a large panoply of IV therapies available, all of which I utilize in the headache clinic. I have listed in Table 1, for rapid reference, all of the IV treatments to be described in detail in the following sections.

IV MgSO4. In many ways, in my head-ache clinic, this treatment is a sort of “opening shot” for intractable headaches, both migraines and not. It can be given alone, or combined with antinauseants (IV metochlopramide, promethazine, prochlorperazine or droperidol) or with IV steroids. There is a substantial literature on use of magnesium intravenously for migraines and cluster headaches.27-30 The original studies by Mauskop and colleagues utilized ion-sensitive Mg++ electrodes to measure ionized magnesium, a technique not commonly available. Magnesium has primary effects as a physiologic antagonist to calcium. It also blocks NMDA-type glutamate excitatory amino acid activity, and nitric oxide synthesis and release, all of which are factors in migraine pathophysiology or maintenance. It augments serotonin which may be a direct means of blocking migraines. Multiple types of headaches, including migraines, migrainous headaches, tension-type headache, and cluster headaches responded to intravenous magnesium therapy.27 Originally, the dosage was 1 gram IV. It turned out that the headache sufferers with the best and longest response to IV magnesium had the lowest ionized Mg++ levels, both for migraines as well as for cluster headaches.30 The editor of this review, Dr. Jeff Unger, along with several of the other authors, have recently summarized their clinical data with IV MgSO4.31

Antinauseants (IV droperidol, metochlopramide, promethazine, prochlorperazine, and ondansetron). Antinauseants have long been used along with acute opiate therapy for headaches and for pain treatment, on the notion that the use of both agents was somehow synergistic. Animal experiments seemed to support this idea, but human studies are not at all conclusive on this point.32 I’ve looked for evidence of this, but it is almost non-existent and, other than nausea being a prominent symptom that accompanies headache, I’m not sure why the older phenothiazines are routinely used with analgesics. Nevertheless, ED treatment of headache most often uses opiates together with antinauseants. In a very large study of ED treatment patterns in Canada and the US for headache, analysis of 811,419 migraine treatments in l998 showed that adjunct anti-emetics were most often given with opiates. Promethazine was used six times more often than dopamine antagonists like droperidol, prochlorperazine or metochlopramide.33 My preference is to use metochlopramide, both IV and IM, as well as PO, as a first-line antinauseant in the clinic and in my patients in general. I believe it works more effectively than the older compounds with far fewer side effects. A paper published in February 2005 in Neurology, described an ED study showing superior effectiveness of IV metochlopramide, 20mg, against 6mg of SQ sumatriptan. Better decreased pain intensity scores and pain-free rates were found in this study.34

Table 1. Medications for Use in the headache clinic
Medication Availability Pulse Oxmonitoring Cost Factor IM Use
MgSO4 Very good Not required Inexpensive No
Antinauseants Very good Not required Inexpensive Yes
Steroids Very good Not required Inexpensive Yes
DHE45 Very good Not required Mod expensive Yes
Depacon Very good Not required Moderate No
Propofol Very good Required* Moderate No
Lidocaine Very good Required* Inexpensive Yes
Levetiracetam Specialcompounding Required Expensive No
Tramadol Specialcompounding Required Moderate No
Ketamine Poor Required* Expensive Yes
Methocarbamol Very good Not required Inexpensive No
*ACLS trained staff and crash cart is recommended on the premises

There is a growing body of evidence that blockade of central dopamine receptor systems can enhance anti-nociception or the pain-relieving analgesic properties of opiates.35-37 One recent study of neuropathic pain suggested that bupropion might decrease neuropathic pain via an effect on presynaptic reuptake of dopamine.38 These properties might explain the ability of dopamine blockers, like metochlopramide or droperidol, to reduce migraine headaches—an effect we and others have noted in the clinic setting in the treatment of migraines.

One of the initial studies using IV droperidol39 used quite high doses (mean = 5.6mg) and reported nearly all of their patients being sedated and over 50% having extrapyramidal symptoms 24 hours after treatment. We repeated a series of patients in our clinic using from one fifth to one quarter of the dose of IV droperidol with only 3% side effects and over 80% success rate in reducing or eliminating refractory migraines.40 A recent double-blind trial of intramuscular droperidol, again using high doses of the medication, showed efficacy; however, the placebo response rate was 57% vs 84% for droperidol. Once again, anxiety, akathisia and somnolence were rated as severe in 30% of patients,41 presumably due to the high doses employed. Thus, keeping doses quite low (around 2 mg total) can be very effective and I have quite a number of patients who use droperidol IM as rescue medication for their migraines—either with migraine-specific therapy or to avoid a trip to the emergency room. I often begin with 0.625mg of IM droperidol, repeated after 20-30 minutes, and once again if needed.

An older ED study using IM prochlorperazine vs metochlopramide showed the former to be more reliable in reducing headache to the endpoint of the study (1 hour). Yet both groups required additional rescue treatment with analgesics (57-79%) after initial treatment with an antinauseant.42 Another ED study compared the efficacy of IV MgSO4 against prochlorperazine in acute headache patients. The study found prochlorperazine to be much more effective with fewer side effects than magnesium.43 My only comment is that the dose of the MgSO4 was rather low compared to our clinic IV doses.

Ondansetron, a very powerful antinauseant often used in chemotherapy regimens has been used successfully in my clinic, 2-4mg IV, as an adjunctive medication for intractable vomiting associated with prolonged migraines. A search of the literature surprisingly revealed very little or no data to support its use in acute or refractory migraines. Indeed, one small study in children during cancer treatment described onset of daily migraine-like headaches.44 All patients had a personal or family history of migraines, however.

IV Steroids. There is very little literature on the use of corticosteroids to treat migraines, although there is more data in the cluster headache field or for treatment of status migrainosus or analgesic rebound headaches.45 Anecdotally, I use dexamethasone in the clinic fairly often for refractory migraines, for helping with detoxification regimens, and for pain flare-ups. This is not necessarily followed by an oral taper. Most often, I give it along with IV MgSO4 as they are both compatible in the same IV bag (unpublished observations). Other authors have published results from their own clinics, showing that dexamethasone was indeed effective in their migraine and status migraine populations.46-47 Other than very rare transient elevations in blood sugar and a tendency to be hungry and have more energy, I see very little in the way of negative effects from a single IV dose (usually 4 mg) of dexamethasone in our headache clinic.

IV DHE. Before we had triptans, the gold standard for treating intractable migraines was dihydroergotamine (DHE), a compound similar to, but very different pharmacologically from, ergotamine. Many people forget that the pharmacologic profile of DHE is predominantly that of a venoconstrictor (as well as an arterial constrictor), whereas ergotamine is a pure arterial vasoconstrictor. Also, ergotamine is fraught with the possibility of rebound migraines and headaches, whereas DHE does not have this property associated with it—even with rather chronic use. DHE can be given IV or IM and has a 10-14 hour half-life. The original IV DHE protocol to treat refractory migraine headaches was introduced in 1986 by Professor Raskin and it became the mainstay of inpatient and in-clinic treatments.48 Typically, it was given every 8 hours with IV metochlopramide, 10mg, for 2-3 days. In retrospect, metochlopramide probably also has a migraine blocking effect as discussed under the antinauseants. Comparisons of this protocol against “typical” treatment with meperidine and promethazine showed similar efficacy with significantly fewer side effects in the DHE/metochlopramide group,49 making it very useful for office-based treatment of migraines. One study evaluated the same protocol in a headache clinic against IV ketorolac and found the DHE protocol to result in a greater degree of improvement and better function clinically.50 Various IV protocols then available for clinic use were subsequently summarized by the same author.51

I introduced the DHE45 protocol to Dallas in 1987 and it has found a lot of use by some of my colleagues who have an interest in treating headache and migraine patients. While I no longer send patients to the hospital, I was previously admitting 150 patients a year for inpatient treatment with 2-4 days of DHE45 (1 mg by slow IV push over 10 minutes) preceded by 10mg of IV Reglan. This was given every 8 hours around the clock while a patient was either detoxed from opiates or a sound sleep pattern was created, often with IV lorazepam. I have since switched to an outpatient protocol where my nurse or I can give two doses of IV or IM DHE/metochlopramide per day for up to three days. The third dose, if needed, can be given at home by the patient or a family member. This results in a tremendous cost and time savings for the patient and for me. In rare cases, the patient can also continue a short run (3-5 days) of 2 IM doses at home each day to break a bad cycle of migraines.

IV Depacon. Sodium valproate (divalproex sodium as an enteric-coated preparation) was approved in 1994 for oral use in the prophylaxis of migraines in the United States. It was the first anticonvulsant molecule to be found useful in treating migraines in a prophylaxis manner.52-54 After a time, an IV version of the valproate sodium was developed and has been used for treatment of seizures. In our search for additional agents to use in the clinic intravenously for intractable migraines and other headaches, we turned to this compound and presented an initial open-label study in poster form.55 Our results showed an impressive reduction in migraine severity, both in this initial trial and in subsequent studies. Soon thereafter, other open-label studies including our own, began to show up in the literature.56-58 documenting efficacy of valproate sodium IV in treating migraines.

Our study was a sample of 85 intractable migraineurs and the response to IV valproate sodium was a 88% reduction in severity of migraine, patient-rated on a 0-10 numeric rating scale. The average dose of valproate was 720mg, 58 given IV over about 50 minutes (100-200mg every 5-10 minutes). One study investigated the use of valproate sodium in initial treatment of chronic daily headache, transformed migraine, and analgesic overuse headaches,59 especially if other agents were not effective. Another study found that valproate sodium was less useful than prochlorperazine in the ED for the headache pain and nausea symptoms.60 A recent study treated mostly chronic daily headaches, chronic tension-type headaches and unclassifiable chronic headaches (67%), with just over 30% episodic migraines. 57.5% of patients treated responded to valproate sodium treatment and the lower efficacy may be due to the nature of the chronic headache population treated in this study,61 We have recently gone back over our initial study data and extracted 23 cases of bona fide status migrainosus from out initial published study sample treated with IV valproate sodium in the headache clinic. This very difficult-to-treat migraine population responded to almost the same degree as the refractory migraineurs, but needed a higher dose of valproate sodium (1017mg) and a longer treatment time (73 minutes vs 50 minutes). Thirteen of the 23 patients rated their migraines as 0/10 in severity after treatment (57%).62

IV Propofol. Sometimes, interesting results are stumbled upon serendipitously, as occurred in the case of the pre-anesthetic agent, propofol. We use this agent routinely in the clinic as a mild sedative prior to epidural steroid and other nerve blocks in a conscious sedation manner. We noted that some patients who had migraines at the time of their blocks would comment on betterment of the migraine before the block was performed but after propofol was given in conscious sedation doses. After researching the literature, we found no other mention of this agent in treating migraines and undertook a formal open-label study in the headache clinic to treat refractory migraines unresponsive to usual abortive approaches. We treated a cohort of 77 patients and the results were nothing short of spectacular. Propofol was the most effective IV agent that we had ever employed, with a 95.4% success rate in reducing ongoing migraine headaches. The total dose was only 120mg, given slowly by IV push 20mg at a time. The most fascinating element in this study was the specific pharmacologic effect of propofol, which has sole effects on subtypes of the GABAA receptor.63 It had me speculating as to the role that this receptor system might play in the maintenance of migraine headaches. Indeed, topiramate has been approved for migraine prophylaxis last year and one of its mechanisms of action is on GABAA receptors. We have also anecdotally looked at small numbers of patients with painful disorders like trigeminal neuralgia and other pain flare-ups and they seem to also respond to propofol.

IV Lidocaine. Lidocaine is an indiscriminate blocker of sodium (Na+) channels and blockade of this system has definite implications for reducing neuropathic pain disorders. Many of the so-called anti-convulsants (better termed neuronal stabilizing agents) include this mechanism of action. All of the same agents have also been shown, at least open-label, to reduce migraines and other headaches.64 We have used IV lidocaine, with pulse oximetry monitoring, in the clinic for years in the treatment of pain and headache flare-ups. The paradigm is to treat very slowly, so as to saturate the Na+ channels and obtain the best possible blockade. Often, the response is short-lived (12-48 hours) and buys time for other treatments to be put in place. Formal trials of IV lidocaine to treat acute migraine headache were published some time ago, and were poorer in outcome than with DHE or chlorpromazine treatment IV,65 or against placebo in a double-blind trial.66 The response to IV lidocaine was better in chronic daily headache in two retrospective studies.67-68 We have recently re-explored IV lidocaine for treatment of refractory migraines and have shown some promising data.69 We will also be describing studies using IV lidocaine for pain disorders in the near future.70

IV Levetiracetam (Keppra™). Our data with the oral form of this neuronal stabilizing agent was the first available anywhere in the treatment of refractory migraine headaches,71 and this agent has a unique mechanism of action that effectively blocks high-voltage calcium channels—another major activity of many neuronal stabilizing agents. Subsequently, we developed an IV form of the same agent with a compounding pharmacy and evaluated levetiracetam IV in the treatment of refractory migraines. More recently, cluster headache flare-ups and pain flare-ups like trigeminal neuralgia and CRPS have also been treated in the clinic.72-73 This is a powerful, non-toxic form of treatment for many difficult pain and headache flare-ups. The manufacturer recently released an IV preparation for commercial use to treat seizures.

IV Tramadol. Tramadol has been available in the US for a number of years and has been used in Europe for over 30 years. A half billion people worldwide have been treated for pain with this agent, whose pharmacologic activity includes opiate-like effects on the mu receptor, as well as weak presynaptic reuptake inhibition of norepinephrine and serotonin (like venlafaxine or duloxetine). We decided to formulate a sterile IV preparation to treat headaches. An IV form is available in Europe and has a fairly extensive literature in treating pain. I had originally published data with the oral form of the medication in treating headaches74 and was impressed by its ability to treat chronic headaches and migraines without the usual bugaboo of tolerance seen with other common opiates. The IV preparation of tramadol turned out to be very efficacious, very well-tolerated and treated refractory migraines and mixed headaches with pain flare-ups,75 and gave me another tool to use in the clinic when other agents fail.

“We treated a cohort of 77 patients and the results were nothing short of spectacular. Propofol was the most effective IV agent that we had ever employed, with a 95.4% success rate in reducing ongoing migraine headaches.”

IV Ketamine. Considering the evidence that excitatory amino acids like glutamate are the “bad guys” in promoting nociception in general and hyperalgesia and possibly allodynia, it is not surprising that agents that antagonize this system might have utility in reducing pain and headache symptoms. Unfortunately, they are the very compounds that block the NMDA family of glutamate receptors in the first place. Either they have low potency, like detromethorphan or memantine, or they have high potency and an extremely narrow therapeutic index like ketamine, MK801, or phencyclidine. Some headache and pain physicians, myself included, tend to think that neuropathic pain, chronic daily headaches and migraines are, underneath it all, very, very similar in their biochemical makeup or underpinnings with respect to cellular mechanisms. The fields of pain and headache management are utilizing common terminologies to describe these convergences. Nociceptive pain, peripheral and central sensitization, windup, long-term potentiation and neuroplasticity are concepts basic to the expression of these disorders. Common neurocellular and neurotransmitter pathways may explain the clinical expression of both neuropathic pain and migraine and associated hyperalgesia and central sensitization.76 On the treatment side of things, why is it that medications with completely different structures but similar mechanisms of action (i.e., propofol and topiramate, each of which act on GABAA receptors) can both reduce migraines and other headaches and pain as well?

An agent active against NMDA-type glutamate receptors that has been shown to decrease migraine attacks when given subcutaneously is ketamine. This anesthetic agent has been little studied thus far but may have theoretical implications for preventing chronic migraines.77-79 One other recent study administered ketamine intranasally to migraine patients who had pronounced and disabling aura. Less than 50% had successful resolution with ketamine.79 In both sets of studies the dose of ketamine was low, but more work needs to be done with this specific blocker of glutamate receptor subtypes. A poster, presented at the International Headache Society meeting in Rome in September 2003, described increased CSG glutamate levels in chronic migraineurs compared to non-migraine controls.80 Further, the patients with migraines and fibromyalgia had even higher levels than patients without chronic pain. Glutamate, with its subtypes of receptor families and pharmacologic targets will be an active area of research and, hopefully, treatment. We have presented our own data for IV ketamine recently for treating refractory headaches,81 and will show additional data for IV treatment of pain disorders82 at upcoming meetings.

IV Robaxin. Although methocarbamol is an older muscle relaxant preparation with uncertain pharmacologic mechanism(s) of action, it is one of the very few available in an IV form and, for this reason, I sometimes utilize it in the clinic to treat migraines and other headaches—especially if accompanied by a lot of neck spasm. I know of no published studies looking at effectiveness of this agent intravenously to treat headaches. Therefore, all my information is anecdotal and rarely do I use it alone but, instead, often use after other agents. I have had about 50 patients over the last 5-7 years for whom addition of methocarbamol is a positive element in their overall headache relief.

Botulinum Toxins. The field of botulinum toxin pharmacology has burgeoned over the last 5-8 years in the treatment of pain and headache, although the first reported decrease in pain due to the toxin was observed in 1986, in a study that originally was written to describe its effects in cervical dystonia; the pain relief effects outlasted the relief of the dystonia.83 By now, there is a wealth of information on this broad topic. Of course, officially, botulinum toxins (type A and type B) BoNTA and BoNTB. are approved by the FDA only for cervical dystonias, including torticollis, strabismus hemifacial spasm, and for blepharospasm. There is a cosmetic use which is approved as well. It should be emphasized that there is no official approval for headaches or pain as yet. Therefore, there are no billing codes for treating these clinical conditions with BoNTA or BoNTB. I am sure that this will occur in the future and it should not dissuade anyone interested in this field from getting appropriate training to use BoNTA/BoNTB.

I have included several general references regarding the use of BoNTA and B including their uses in painful and headache disorders.84-87 Basically, the botulinum toxins, when given intramuscularly, act as chemodenervation molecules by attaching to acetylcholine-containing motor nerve fibers and preventing release of the neurotransmitter needed to initiate contraction of striated muscle.88 The effect is long-lived, often months in length. A number of recent studies have demonstrated the efficacy of botulinum toxin (mostly type A) in the treatment of headache disorders, including migraines.89-92

The traditional use of BoNTA/B preparations involves injection of the toxin intramuscularly. This is based on its time-honored method of use for muscular and neuromuscular problems, and it may, or may not, be the most optimal way to administer the medication. Treatment with toxins is for headache patterns that outrun prophylaxis therapy or where there is escalating and more frequent use of triptan medications. Placement of injection sites is dictated by the patient’s headache location. A patient who has the majority of their migraine headaches near the temporal area—with the headache radiating to the back of the neck on the same side, and with severe neck tightness or spasm—will likely get injected near these areas. This would be a ‘follow the pain’ approach.

The risks of treatment are extremely low and almost nonexistent. Other than 2-3 cases of redness or itching at the injection site, or a transient flu-like (temporary) sensation, I have encountered no side effects from the toxin. The upside of the botulinum toxin therapy is the long time-course of relief of muscle spasm and pain/headache. For coding purposes, we focus on the muscle spasm aspect—in itself a very good reason for the treatment.

The cost of the medication is also an issue: at $446 per 100 units of botulinum toxin, type A, (Botox™), and an equivalent amount for the type B toxin, it has to be factored into the therapeutic equation. Will the patient save more money on fewer “triptan” doses and less prophylaxis treatment? There is also the cost of obtaining training in performing the injection. So, it comes down to the practitioner who has a high-enough interest level in this tool and the right patient population.

A new set of observations is evolving on precisely where to administer the botulinum toxins to get an anti-pain effect. I was intrigued by a report of radio-labeled toxin that was injected into the peripheral muscles of a cat and, 2 weeks later, radioactivity was found in the spinal cord contralateral to the injected side!93 Why was the radioactivity able to track back to the spinal cord and even cross over? I took a small sample of patients with pain or migraines that began on one side at the base of the neck and gave the BoNTA or BoNTB intradermally by raising a skin wheal in the area over where the greater and lesser (GON and LON) would be present deep to the skin (see Figures 1 and 2). Patients began to report that their migraines and muscle spasm were reduced. Initial data were presented for both BoNTA and BoNTB,94-95 and recently in a formal publication.96 A double-blind trial has been finished with intradermal BoNTB for migraines of cervical origin and the data has been presented.97 I have gathered similar data with intradermal BoNTA/B in scar pain, RSD, diabetic neuropathy, carpal tunnel and TMD98 (see Figures 3-6). A double-blind study with intradermal BoNTA to treat carpal tunnel syndrome has just been finished and the data is being analyzed.

It appears that the intradermal method of administration of BoNTA/B may have some cellular and neuropharmacological basis as recent studies in different preparations have demonstrated that the toxin, type A, blocks the release of several transmitters involved in the pain and migraine cascade. Blockade of Substance P, Calcium gene-related peptide (CGRP) and glutamate have all been demonstrated.99-101 These exciting insights into the nature of botulinum toxin’s ability to reduce headache and pain are a new chapter in the use of these compounds and will be the subject of new studies.

Figure 1. Location of intradermal BoNTA/B injections at base of neck (usually unilateral) Figure 2. Right side intradermal BoNTA/B injection for spasm, pain/headache Figure 3. Location of intradermal injection sites for TMD Figure 4. Intradermal BoNTA/B injection for TMD Figure 5. Location of intradermal BoNTA/B injections for carpal tunnel syndrome. Figure 6. Intradermal BoNTA/B injection for carpal tunnel syndrome pain

Conclusion

The future of aggressive pain and headache treatment will reside in the sphere of the specialist’s clinic. This is a cost- and time- effective mode of treating intractable pain and headaches. Compared with the treatments commonly available in the emergency department, the outpatient clinic can offer a wider variety of effective and definitive treatments and thus offer patients a maximum degree of success for control of their intractable pain symptoms.

This article has discussed intravenous (IV) medication treatment strategies, and our results with these in the pain and headache clinic setting. Our success rates, defined as a greater than 50% reduction in presenting symptoms, are in the 96% range.

I have also discussed the use of botulinum toxins for the treatment of pain and headaches in the outpatient setting, perhaps in a new controversial manner. It is expected that future studies will improve our understanding of it’s mechanism of action and increase it’s use for this purpose. Stay tuned.

With so many different combinations of pain presentations (e.g. refractory migraines/headaches with pain flare-up with varying levels of nausea, or accompanying muscle spasm, or burning, etc.), it seems as if virtually every combination of IV medications at our disposal has been tried or given in our clinic at one time or another. Of course, we make every effort to use one medication at a time and to carefully document the percentage pain reduction of that single agent. As you can imagine, agents that have worked successfully, perhaps many times before, might not work in the next particular situation and so we always have a “game plan” for the next agent. The key is to have a wide and varied repertoire of interventions to address each unique patient’s pain presentation.

Last updated on: December 26, 2012
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