A.
Headache (tension-type and/or migraine) on 15 days per month for at least 3 months
B.
Occurring in a patient who has had at least five attacks fulfilling criteria for 1.1 migraine without aura
C.
On 8 days per month for at least 3 months, headache has fulfilled C1 and/or C2 below—that is, has fulfilled criteria for pain and associated symptoms of migraine without aura
1. Has at least two of “a” through “d”
a.
Unilateral location
b.
Pulsating quality
c.
Moderate or severe pain intensity
d.
Aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing stairs)
Has at least one of “e” or “f”
e.
Nausea and/or vomiting
f.
Photophobia and phonophobia
2. Treated and relieved by triptan(s) or ergot before the expected development of C1
D.
No medication overuse and not attributed to another causative disorder
Table 2.2
Proposed criteria for definition of refractory migraine and refractory chronic migraine. (Based on Ref. [95])
Criteria | Definition |
|---|---|
Primary diagnosis | ICHD-II migraine or chronic migraine |
Refractory | Headaches cause significant interference with function or quality of life despite modification of triggers, lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy |
Failed adequate trails of preventive medicines, alone or in combination, from at least two of four drug classes: Beta-blockers Anticonvulsants Tricyclics Calcium channel blockers | |
Failed both a triptan and DHE intranasal or injectable formulation Failed either nonsteroidal anti-inflammatory drugs or combination analgesics | |
Adequate trial | Period of time during which an appropriate dose of medicine is administered, typically at least 2 months at optimal or maximum tolerated doses, unless terminated early due to adverse effects |
Modifiers | With or without medication overuse, as defined by ICHD-2 With significant disability, as defined by MIDAS > 11 |
Challenges of Refractory Migraine
RCM presents a number of major challenges, with each challenge necessitating a change in approach [42]. These challenges include:
What role does disability play, and should disability help to define RCM?
What constitutes resistance to treatment(s)?
There are no accepted, identifiable biological marker(s) for RCM. Therefore, how does one diagnose RCM?
The degree of disease can change over time, improving or worsening. What role does the varying severity play?
There are various subsets of RCM—posttraumatic headache, RCM with or without medication overuse headache (MOH), RCM with or without major psychiatric comorbidities, etc. How is the diagnosis and treatment affected by these subsets?
How does the treatment differ for various ages: adolescent versus young adult versus middle age versus older ages?
Pathophysiology
We are just beginning to look beneath the surface of what causes RCM [28]. Some of the issues include:
What is the role of genetics in drug resistance and inheritance of chronic headaches?
What structural changes (in white matter or iron deposition) play a role?
What role does central sensitization and neuroplasticity play?
How much involvement is peripheral versus central nervous system (CNS)?
How does MOH affect the structure and function of the nervous system?
What is the physiologic impact of psychiatric comorbidities? Do depression and/or anxiety fuel the headaches?
Continuing research is critical to answer these questions.
Several risk factors are posited to drive the development of RCM. These include lifestyle issues such as medication overuse, sleep habits, caffeine overuse, and obesity [45]. While pharmacotherapy may be the cornerstone of treatment, other modalities are no less important. The patient must manage his or her triggers with regard to sleep, food, and caffeine intake. Exercise and weight reduction are encouraged. Stress, another major trigger, may be relieved by practicing biofeedback and/or yoga. Depending on the origin of the pain, physical therapy and massage may help. Problems with the teeth, jaw, eyes, and neck should be addressed.
Medication Overuse Headache
MOH is a critical issue that must be addressed early in the treatment of any form of headache [44]. The overuse of abortive migraine medication, used at the onset of a headache, is a major risk factor for the progression of migraine into RCM. Some patients have medication overuse without an increase in headache. In others, overuse of abortive medications is the principal cause of the headaches.
The criteria for diagnosing MOH are listed in Table 2.3. Note that the headache progresses, instead of subsiding, over time, and the calls for prescription refills will become more frequent with the progression. When treating patients with MOH, the offending drugs will need to be withdrawn or limited. While we do not know, with any certainty, the percentage of RCM patients in whom MOH is a major contributor, we know that MOH should be one of the first considerations when a patient presents with worsening headaches.
Table 2.3
Medication overuse headache
Headache present on > 15 days/month |
Regular overuse, > 10 days/month or 15 days/month, depending on the medication type The overuse is for at least 3 months |
Headache has developed or markedly worsened during medication overuse |
While medication overuse is common, not all overusers suffer from increased headaches as a result of the abortive medications. The current definition of MOH conflates medication overuse with MOH, and, as a result, many patients are incorrectly labeled as having MOH.
Treatments for RCM
There is no algorithm for migraine treatment. The choices of medication will vary for each patient, depending on headache severity and comorbidities. For an RCM patient, the choice of therapy depends on a number of variables, including age, psychiatric comorbidities (for more on psychiatric comorbidities, see related article), tendency towards addiction, sleep, medical conditions, etc. Comorbidities often steer where we go with medications: Conditions such as irritable bowel syndrome (IBS), fatigue, and psychiatric conditions have to be considered. Of course, the familiarity and confidence with a particular therapy on the part of the treating physician plays a major role in selection. It is also crucial to resolve medication overuse, and eliminate rebound in all RCM patients. For the remainder of this chapter, the author has highlighted a number of possible approaches (opioids, onabotulinum toxin, daily or frequent triptans, stimulants, monamine oxidase inhibitors (MAOIs), injections, and miscellaneous) , some of which may be combined.
Opioids
In my practice, long-acting opioids (LAOs) are the most commonly used approach for RCM. The best candidate for LAOs is the person who has done well on short-acting opioids (SAOs) and who does not have characteristics of a personality disorder (PD).
Phases in Opioid Use
There are three distinct phases in the use of opioids. The first phase is the initiation of treatment. This includes the initial screening and risk assessment, the doctor’s decision as to which opioid to use, and the doctor–patient discussion and signing of an opioid agreement. Prior to initiation of LAOs, an assessment of the following should be done: pain level, moods, social and family functioning, work status, physical functioning, and activities of daily living [27].
The intermediate phase comprises the diligent monitoring of the patient while he/she is on the opioid. This must include ongoing assessment of the patient’s pain level and overall functioning, with a watchful eye for signs of abuse. On return visits, the physical exam needs to assess for slurring of words, abnormal gait, and pupillary abnormalities. Do not assume that low-risk patients will never abuse the opioids. During the maintenance phase of opioid prescribing, it is remarkable how many seemingly low-risk patients misuse the drugs.
Patients usually respond fairly quickly to an opioid; if they have not responded by 2–4 weeks on a low dose, there usually will not be an adequate response [88]. If patients do not report an improvement in functioning, or if functioning declines, consideration should be given to withdrawal the opioid. Some patients have an improvement in pain but a decline in physical activity, possibly due to sedation or other opioid-related side effects.
The third phase is switching or withdrawing the opioids when abuse has occurred or there is lack of efficacy. Withdrawing or switching an opioid may be exceedingly difficult in some patients. Each of these phases involves a learning curve on the part of the practitioner and proper documentation by staff members.
In my experience, using higher doses of the opioid rarely works out in the long term. Higher doses place the patient at an increased risk for addiction and abuse as well as complications from withdrawal. It may be thought that, given the great variation in individual responses, the opioid should be increased or “pushed” to whatever level is beneficial. However, medical and regulatory considerations should be limiting factors in keeping the opioid dose at a low level.
The choice of opioid may be key; some have been shown to have less abuse potential. The once- or twice-daily, long-acting morphine preparations have not been subjected to widespread abuse. Methadone may be more effective than some of the other medications, but has a litany of problems associated with it. Besides the social stigma, high protein binding is a risk, which may lead to irregular drug levels, difficulty with withdrawal, and an increased risk for sudden death [64]. If methadone is used, it should be started at a very low dose of no more than 5–10 mg a day, and titrated slowly. Patients placed on methadone require close monitoring, and other sedatives must be reduced or discontinued. The usual dosing range in my practice is:
Methadone, 5–40 mg per day
Morphine, 20–90 mg per day
Oxycodone, 20–60 mg per day
Hydrocodone, 15–40 mg per day
Some type of written opioid agreement should be part of the doctor–patient alliance, although there is a lack of evidence that these agreements do much good for the majority of the patients. There is no standard opioid contract; practices should adapt one for their own purposes. There are several resources on opioid agreements (www.painmed.org; www.ampainsoc.org; www.fsmb.org; www.usdoj.gov/dea). In addition, there is an excellent article on agreement contracts by Fishman [25].
The treatment of breakthrough pain is controversial. Most of the breakthrough studies have been concerned with cancer pain, where the average number of breakthroughs is 4 per 24 h [111]. For patients with noncancer breakthrough pain, such as chronic daily headache, I tend to minimize the total opioid and avoid layering pain medicines on top of each other. Prescribing short-acting medications for chronic headaches greatly increases the abuse rate. The occasional patient can remain on a low dose of the LAO, with one or two SAOs per day, but, in general, clinicians should try to avoid SAOs .
Long-Acting Opioids
The following summarizes certain LAO studies and describes guidelines for using LAOs in chronic migraineurs.
In 1997, Saper and associates assessed refractory chronic daily headache with scheduled LAOs, particularly methadone [91]. There was a small subset of patients who did well. Subsequently, Saper and his associates soured on the use of the opioids.
Similar results were obtained from Rothrock [87]. An unpublished study from Rothrock indicated that of the CM patients who were responsive at 2 months to methadone treatment, more than 70 % continued to maintain a response at 1 year [88]. Rothrock found that patients tend to either respond to relatively low doses or not at all. His studies also indicated that virtually all of the positive responders, when tapered off of the methadone, relapsed into their frequent headache patterns [88].
In 2007, our group evaluated 115 patients with RCM who were treated with LAOs during a 6-year period. This was a select group of patients who previously had all done well on SAOs . Avoidance of opioid-induced hyperalgesia (OIH) is important in patients taking opioids in the long term; however, all of the patients in this study already had been on SAOs for at least 1 year [76].
Sixty-five percent of the patients did well for at least 9 months on the opioid. This was a significantly higher rate of success than that found in a previous study (13 %) that used a different standard of success [65]. The average duration of use of the opioid was 4.5 years. Forty-four percent of the patients reported adverse events. Patients with an increased chance of success included younger patients, patients with high coping skills, and those without a history of opioid abuse. Predictors of failure were comorbid PDs, older age, and, in particular, previous abuse of the SAOs. In this study, anxiety, depression, bipolar depression, attention deficit disorder (ADD), exercise, work status, disability, fatigue, and cigarette smoking did not significantly change the long-term outcome.
SAOs Versus LAOs
The term SAO generally refers not only to how long a drug carries the desired effect but also the speed of onset of the drug and how fast it drops off toward the end of the dose. Quick onsets and fast drop-offs are major determinants for abuse [36]. SAOs are not necessarily quick-onset medications. Most oral SAO tablets are slow to take effect. A short duration of action then leads to frequent administration by the patient, and overuse may occur. However, it has not been proven conclusively that SAOs lead to more abuse than LAOs . Although certain long-acting drugs have been easily abused, such as oxycodone CR, it is the person, not the drug, who governs abuse. While some abusers have only one drug of choice, many will tend to abuse a succession of drugs.
Several previous studies have evaluated daily opioids for severe chronic daily headache [63, 87, 91]. While success rates have been relatively low, they represent patients who have failed the usual ministrations, and who have few options available. Table 2.4 outlines the advantages and disadvantages of LAOs.
Table 2.4
The pros and cons of long-acting opioids
The advantages of long-acting opioids include |
Avoidance of the “end-of-the-dose” phenomenon, with mini-withdrawals throughout the day |
Consistent dosing one or two times daily, which decreases the obsession with the next dose |
Maintenance of stable blood levels |
Avoidance of acetaminophen, aspirin, and NSAIDs that are included in many short-acting preparations |
Probable diminished risk of significant abuse |
Better compliance, with less psychological dependency on the drug |
The disadvantages of long-acting opioids include |
Social stigma |
Fatigue and constipation |
Difficulty in obtaining scripts, with no refills available |
Need for frequent office visits and monitoring |
Risk of opioid-induced hyperalgesia |
Risk of abuse, although probably less than with short-acting opioids |
Interactions with other sedating drugs and alcohol |
Risk for overdose |
Opioid Abuse
Opioid abuse is much more common than true addiction. In general, using opioids for therapeutic reasons other than pain constitutes abuse. In a headache practice, the most common reasons for abuse are using the opioids to alleviate moods, anxiety, or depression.
Patients in our previous study were assessed for behaviors typical of opioid abuse or overuse. The criteria that we used included: early refill requests, dose escalations, insistence on increasing doses, abusive treatment of the staff regarding refills, false reports of stolen or lost medications, using the opioid for depression or anxiety , using the opioid for other pains not discussed with the physician, receiving similar medication from other physicians, unexpected or abnormal urine screening test results, using illicit drugs or alcohol, missing, canceling, or refusing appointments, selling the drugs, obtaining opioids from nonmedical arenas, frequent emergency room (ER) visits for opioids, hoarding, forging or altering scripts, borrowing or stealing similar medications from family and friends, physical signs of overuse or addiction, and calls to the physician from family members with concerns about patient overuse [11, 110].
There is a range of abuse, from the person who samples his spouse’s codeine prescription once in a while to the addict who obtains hundreds of opioid tablets from the Internet. We cannot paint all abusers with one broad brush. Some situations need watching, such as the patient who took her mom’s pills because she had excess pain; this behavior is a red flag and the patient may be an abuser. For a different patient, one who already has been prescribed low-dose, long-acting morphine, the discovery of undisclosed opioid prescriptions from other sources must be regarded as severe abuse. In this situation, discontinuation of the opioids is necessary.
It is not always clear how serious the abuse is. Minor aberrant behaviors often are overlooked. It is not as if any one aberrant behavior warrants immediate discontinuation of an opioid, but most of the serious overuse situations follow a number of previous minor abuse occurrences. Physicians must pay attention to red flags, particularly those that arise early in the relationship with the patient. In my experience, pain patients who raise objections to urine tests usually have a drug problem. Specimen collections should be random and not scheduled. Urine testing serves two purposes: To identify other substances that are present but should not be and to measure the levels of the prescribed substance for compliance. When there is no opioid present, there sometimes is laboratory error or test insensitivity, but it may be that the patient has been binging early on and has run out of drugs before the visit [30]. Another possibility is that the patient is selling the drugs.
In those who self-medicate, a drug is used for a purpose other than the intended one, such as using an opioid as a mood stabilizer or enhancer. Opioids can be both calming and stimulating, often giving a brief burst of energy followed by a tranquil period. Chemical coping is all too common, but is poorly understood and under-researched [62]. All addicts are chemical copers to some degree, but not all people who cope chemically are addicts. The person who uses one or two pills of hydrocodone a day for stress and anxiety is not an addict by definition but is certainly using chemicals to cope. The severe patients basically live for the drug; their lives are controlled by its procurement, and they have few coping skills outside of using the drug [56]. They will self-escalate their drug use, particularly during periods of high stress.
As much as 35 % of patients with chronic pain may fall under the definition of chemical copers [37]. There are gender differences, with women using the substances primarily for anxiety, stress, and depression. Women are at somewhat of an increased risk for chemically coping than are men [56]. Men may use the drugs for anxiety and depression, but they also use them out of boredom, particularly when they are disabled by their pain. For some men, there is a strong relationship between substance abuse and sensation seeking [56].
While physical dependence and tolerance are to be expected with long-term opioid use, addiction is not. Addiction constitutes a biologic and behavioral disease. Most abusers can stop using the drug when harm occurs, but an addict cannot. Whether a patient with previous addictions should be treated with LAOs is a complicated issue. It should be approached on a case-by-case basis and depends on a number of factors. Among the considerations:
What substances were abused?
How many years has the patient been clean?
Has the patient successfully completed treatment for addiction?
What is the quality of the patient’s support system?
Does the patient have any comorbid psychiatric conditions [110]?
What are the patient’s risk factors?
Previous studies have indicated that risk factors for opioid abuse include cigarette smoking, previous drug abuse, a strong family history of drug abuse, stress, young age, early sexual abuse, poor support, low level of functioning due to headache or other pain, pain embellishment, and certain psychiatric conditions [6, 22, 94].
A National Institute of Mental Health (NIMH) analysis identified certain problems that carried an increased risk for substance abuse [54]. Of patients with anxiety, 25 % had a substance use problem, as did 33 % of those with obsessive–compulsive disorder (OCD), and 61 % in the bipolar I category. Unipolar depression also carried a higher risk, but not as much as bipolar disorder . Among PD patients, Webster found that 84 % of those with antisocial PDs were substance abusers [110]. Also, patients with somatization are probably at a higher risk. In a study by Biederman et al., untreated attention-deficit hyperactivity disorder (ADHD) in older adolescent boys carried a 75 % risk for substance abuse, whereas those with treated ADHD in this age group had a 25 % risk. The boys without ADHD had an 18 % overall abuse rate [7].
As noted, our study indicated that those with PDs were at an increased risk for abuse but that other psychiatric conditions did not lead to more abuse [76].
Successful Management of LAOs
The physician must have knowledge and experience in the use of these drugs. The patient has to be reliable and well-known to the practitioner. Many of the problems occur with new patients; it is prudent to wait several visits before prescribing LAOs—after the physician can establish that there has been little or no previous abuse.
In our practice, patients must have demonstrated an adequate response to SAOs . To avoid OIH, we restrict use to patients who have received SAOs for 1 year or more. The patient must truly be refractory to the typical ministrations, with multiple adequate trials of the usual preventive medications. Previous abuse of opioids should exclude patients from this treatment approach. In this author’s view, previous abuse of SAOs almost always leads to abuse of the LAOs. Pseudoaddiction certainly is encountered, but it seems to be rare in headache patients. Be wary of the patient who claims he or she can tolerate almost no medications except for opioids.
In older patients, particularly those over age 65, the brain has lost the ability to do the “neuronal gymnastics” necessary for the development of tolerance to the analgesic effect. Therefore, older patients may remain on the same low dose for a number of years. In contrast, the use of opioids in patients under 30 years of age should be restricted because younger patients are more likely to develop tolerance to the analgesic effects. If a younger patient fulfills all the requirements, such as truly being refractory, is normal psychologically, and is at low risk for addiction, he or she may be the exception to the age rule.
Management of those with CM involves a biopsychosocial approach. Patients must not rely on the drug to function. While medications may be a mainstay of therapy, other interventions must be employed. Active coping should be strongly encouraged with each visit, and may involve a variety of approaches, including seeing a psychotherapist, physical therapist, or other practitioners, or using self-help approaches such as exercise or biofeedback. Passive coping is a major predictor of disability in chronic pain patients. Patients who rely only on opioids have less of a chance of sustaining long-term relief. Even though pharmacotherapy is the cornerstone of treatment, it is only part of a more comprehensive plan.
Botulinum Toxin Injections
Onabotulinum toxin type A (Botox, Xeomin, and Dysport) has been used as a migraine and chronic daily headache preventive since the 1990s [5]. Botox is the only brand that is Food and Drug Administration (FDA) indicated for CM.
The results of studies have varied widely. Two phase III studies (Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) 1 and 2) with 1384 CM patients found onabotulinum toxin (specifically the brand Botox) useful for improving functioning and reducing disability. One of the studies was very positive in reducing headache days [58]. The preponderance of evidence points to onabotulinum toxin as being safe and efficacious, and this author concurs.
There are a number of possible explanations as to why onabotulinum toxin may alleviate pain. One of its mechanisms of action is that it is anti-inflammatory at the neuronal level. Onabotulinum toxin may block the release of substance P. More importantly, it may also inhibit the level of secretion of calcitonin gene-related peptide (CGRP) [5]. CGRP has been recognized as a key inflammatory mediator, a vital cog in the cascade leading to headache. Efforts are underway to develop drugs that are CGRP antagonists. Onabotulinum toxin also may block the release of certain other neuropeptides that contribute to the “inflammatory soup.” This neuropeptide blockage and onabotulinum toxin’s inhibitory effects on the excitatory neurotransmitter glutamate result in a lessening of peripheral sensitization.
With the use of onabotulinum toxin, there is also a decrease in central sensitization [55]. Relatively few other compounds have an effect on central sensitization, which is so vital to the pathophysiology of CM.
As with a number of migraine treatments, the results of onabotulinum toxin studies vary. A number of variables may explain some of the differences, including [5]:
Headache severity, chronicity, and degree of refractoriness
Medication overuse
Different types of pain (“imploding” vs. “exploding”)
Different methods of assessing outcomes
Different numbers of units of onabotulinum toxin used and different locations of injections.
In a number of onabotulinum toxin studies, the high placebo response rate has been difficult to overcome in proving efficacy. The optimal mechanics of onabotulinum toxin administration are still a work in progress [14, 97]. The FDA’s indicated dose for Botox is 155 units, administered in 31 injections about the head. Some patients do well with much less, which is off-label.
For some patients, we “chase the pain” and administer additional injections around the area of pain, which is also off-label. For those with occipital pain, posterior injections may be very helpful. If patients do not respond to the first treatment, it is worthwhile to repeat onabotulinum toxin at least once more. Onabotulinum toxin is expensive but relatively safe. It may be combined with various medication approaches.
Side effects to onabotulinum toxin tend to be minimal; occasionally patients experience a mild droop of one eye. Some have reported numbness or other sensations around the areas of injection. Generalized weakness should not occur with the low doses that are used. On occasion, patients experience an increase in headaches for a short time.
Daily or Frequent Triptans
It has been over 20 years since triptans were first introduced, and they appear to be much safer than was originally thought. Very few serious adverse events have been reported, considering that more than 100 million patients have taken triptans. Several studies have described the use of daily triptans for the preventive treatment of chronic daily headache [76, 73]. Some patients respond only to triptan medications—sumatriptan (Imitrex, Alsuma, others), naratriptan (Amerge, others), rizatriptan (Maxalt, others), almotriptan (Axert), zolmitriptan (Zomig, others), frovatriptan (Frova), and eletriptan (Relpax). Zecuity is a sumatriptan skin patch.
Short-lasting adverse events are often encountered with triptan use. These include paresthesias, fatigue, chest heaviness, and jaw or neck discomfort [15]. Chest symptoms are, with rare exceptions, not of cardiovascular origin. Echocardiography and electrocardiography generally have been normal after triptan use, even in the presence of chest symptoms.
The primary issue with frequent triptan use, assuming rebound headache is not present, is long-term adverse events. Chronic ischemic changes, valvular abnormalities, and fibrosis are theoretical considerations. Cardiac ischemia due to triptan use is rare [15], and, despite widespread triptan use, the number of adverse cardiac events has been limited. These risks have not been systematically studied, however. The number of patients throughout the world who have used triptans on a near-daily basis is unknown. Until these patients have been studied, it is reasonable and prudent to do cardiac monitoring, as well as hematologic tests.
To study the cardiac safety of frequent triptan use, we studied patient who “on their own” had discovered that daily use of a triptan would alleviate headaches for most or all of the day [73]. Most patients in the study had a long history of headaches that were refractory to usual medications. Most of the patients had been using frequent triptans, prescribed by their primary care physician. A minority of our patients had increased the amount of triptans they used on their own.
Patients were withdrawn from triptans to determine if rebound headache was present. The only patients who continued on triptans were those who had been determined truly to be refractory to other approaches, experienced no or minimal side effects, had rebound headaches excluded, and signed a “Frequent Triptan Informed Consent” form. A summary of patient dose and usage can be found in Table 2.5.
Table 2.5
Characteristics of daily triptan use among 118 patients
Routine laboratory (hematologic) tests, including complete blood counts and chemistries, were done, and no abnormalities were felt to be due to triptans. Electrocardiograms (ECGs) were performed on all of the 118 patients, and 8 patients (7 %) had abnormal findings that were determined not to be from the triptan. Echocardiograms (with Doppler) were done on 57 of the 118 patients (48 %), and 10 of those patients (17 %) had abnormal findings. The attending cardiologist did not feel that any of these abnormalities were due to triptan use. Twenty patients underwent stress tests, and all were normal [73].
Of the 118 patients, 9 felt that the triptans contributed to fatigue; 5 had mild chest tightness at times that was possibly due to the triptans, but cardiac disease was ruled out; and 3 felt that the triptans contributed to nausea [73].
Because the patients in the study decided to use triptans on a daily basis on their own, adverse events would be expected to be low. If patients were not tolerating the medication well or were having significant adverse effects, they would not choose to continue the triptan on a frequent basis. There were no adverse consequences from frequent triptan use over a prolonged period. So, frequent triptan use is not ideal, but may actually be safer than some other approaches. Of course, patients must accept the possibility of the (rare) serious side effect.
Stimulants
When prescribed for headache patients, stimulants may be beneficial for various comorbidities, such as ADHD , depression, and fatigue. In addition, stimulants do not cause the weight gain that is seen with a number of other headache preventive medications. Amphetamines have been shown to possess intrinsic analgesic properties, primarily through brain catecholamine activity. They also intensify the analgesic effects of certain opioids [21]. Stimulants have been used to counteract the sedation encountered by opioids. An excellent review article on stimulants as adjuncts for opioids concluded that “evidence suggests that amphetamine drugs may enhance the effect of opioids and, at the same time, decrease somnolence and increase cognitive performance [17].”
As a group, CNS stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity [24]. Caffeine, the most widely consumed stimulant in the world, is believed to have several mechanisms of action in the prefrontal cortex and other areas of the brain. These include translocation of extracellular calcium, inhibition of phosphodiesterase, and adenosine receptor antagonism, resulting in decreased fatigue and increased mental alertness [24].
Nicotine, the active ingredient in tobacco, specifically stimulates nicotinic receptors in the autonomic ganglia, resulting in euphoria, arousal, relaxation, and improved attention, learning, problem solving, and reaction time [24]. However, in very high doses, nicotine causes blockade of autonomic ganglia, resulting in respiratory depression and severe hypotension.
Amphetamine and its derivatives, such as methylphenidate, demonstrate indirect CNS and peripheral nervous system (PNS) effects similar to cocaine. Like cocaine, they initially increase levels of catecholamines. However, amphetamines do this by a different mechanism of action. They accomplish this effect by causing the release of intracellular stores of catecholamines and inhibiting monamine oxidase (MAO) [24]. The major cause of the behavioral effects of amphetamines is thought to be due more to release of dopamine than norepinephrine [24]. This, ultimately, results in increased alertness, decreased fatigue, decreased appetite, and insomnia, as well as the usual “fight or flight” response that is characteristic of adrenergic stimulation in the PNS.
Amphetamines have been known to possess independent analgesic activity, possibly due to release of norepinephrine. The effect was felt to be about the same as that of ibuprofen. As noted, stimulants may potentiate the analgesic actions of opioids [17]. The most commonly studied combination has been dextroamphetamine and morphine. Methylphenidate also has been studied as an opioid adjunctive medication. In one small study, the use of dextroamphetamine for patients with tension and migraine headache was assessed. It concluded that dextroamphetamine was viable as a preventive medication for chronic tension and migraine headaches in some subjects [32]. In another case report, a man was successfully treated with methylphenidate for his refractory episodic cluster headaches [52] .
One of our previous studies assessed 73 chronic migraineurs who had been prescribed stimulants in addition to their other medications. While the stimulants were primarily prescribed for certain comorbidities, their effect on headaches was also assessed. Seventy-five percent of the patients who were placed on the stimulants remained on them for at least 9 months; 34 % of the patients both remained on the stimulants and reported positive efficacy with regard to headache; 41 % of the patients suffered at least 1 adverse event, whereas only 2 patients abused the stimulant [86].
Advantages of stimulants include enhanced cognition and alertness, with no weight gain. Disadvantages primarily revolve around the side effects, such as anxiety or insomnia. Abuse certainly may occur, but it is uncommon in adults. Stimulants should be considered in patients with certain comorbidities. The few studies conducted to date have indicated a positive role for stimulants, but further studies on stimulants for headache would help to clarify that role.
Monoamine Oxidase Inhibitors
For those with RCM and unipolar depression, monoamine oxidase inhibitors (MAOIs) may be of help. MAOIs sometimes are effective for treatment-resistant depression [40]. They are also effective for alleviating anxiety. MAOIs were commonly prescribed in the 1980s, but with the advent of selective serotonin reuptake inhibitors (SSRIs) and triptans, they fell out of favor. The available literature on MAOIs for headache treatment dates to the 1970s and 1980s. For a select group of RCM patients, the MAOIs greatly enhance QOL. At this point, I believe that MAOIs are underused.
The traditional, classical MAOIs form an irreversible complex with the enzyme monoamine oxidase. Monoamine oxidase is located in a number of tissues, including the brain. The mechanism of action is most likely receptor-mediated pre- and postsynaptic events, not simply an increase in serotonin [40]. The traditional MAOI phenelzine has been the one most commonly used for headache.
The transdermal selegiline patch (Emsam) is a selective MAO-B inhibitor that does not require patients to eat a tyramine-restricted diet, at least in the lowest (6-mg) dose. Another nontraditional reversible MAOI is moclobemide, which is not available in the USA. Moclobemide has fewer dietary and medication restrictions than the classic MAOIs. The efficacy of these nontraditional MAOIs is not as clearly established as the more traditional MAOIs (phenelzine) [41].
Careful patient selection is crucial when using the MAOIs. Patients need to carefully observe the restrictions on diet and medications. I usually prescribe low doses of phenelzine and start patients with 15 mg at night, increasing after 1 week to 30 mg at night. If no response is noted after 3–4 weeks, I usually increase the dose to 45 mg at night; 75 mg is the usual maximum dose. By always taking the MAOI at night, the patient is less likely to encounter a food interaction. Side effects include insomnia, weight gain, sedation, and orthostatic hypotension. The MAOIs have a reputation as being somewhat dangerous and difficult to use, but they usually are well tolerated.
The previous MAOI diets were overly restrictive. The risk of most foods was based on anecdotal cases. Newer evidence-based diets are easier to follow (Table 2.6) [60]. The hypertensive crisis that may occur with a food interaction is due to a number of factors, primarily the amount of tyramine absorbed into the bloodstream. The tyramine content of food has been difficult to accurately establish. When patients consume phenelzine at night in low doses and avoid the major tyramine-rich foods, interactions are less likely.
Table 2.6
Sunnybrook health center MAOI diet
Food group | Food to avoid | Food allowed |
|---|---|---|
Cheese | Mature or aged cheese, casseroles made with these cheeses; all others except listed in “allowed” column | Fresh cottage, cream, and ricotta cheese and processed cheese slices; all fresh milk products |
Meat, fish, poultry | Fermented/dry sausage, pepperoni, salami, mortadella, improperly stored meat, fish, and poultry | All fresh packaged or processed meat, fish, and poultry, stored in refrigerator and eaten as soon as possible |
Fruits and vegetables | Fava or broad bean pods, banana peel | Banana pulp, all others, except those listed in “avoid” column |
Alcoholic beverages | All tap beer | Alcohol: no more than two domestic or canned beers or four oz. wine a day |
Miscellaneous foods | Marmite yeast concentrate, sauerkraut, soy sauce, and soy condiments | Other yeast extracts, soy milk |
Serotonin syndrome may occur due to the administration of serotonergic drugs (i.e., SSRIs) and MAOIs. Other drugs that should be avoided include amphetamines, sympathomimetics, pseudoephedrine, certain opioids (meperidine), dextromethorphan, and others. Most triptans are not combined with MAOIs, but low doses of triptans (frovatriptan and several others) may be used with caution.
For patients suffering from both refractory chronic headache and treatment-resistant depression, MAOIs may offer some measure of hope and are not as dangerous as their reputation might imply.
Injections and Nerve Blocks
Various injections and blocks are used for refractory headache . For frontal headaches, sphenopalatine ganglion (SPG) blocks may be useful. Posteriorly, occipital injections are used. For cervical and occipital pain, various cervical blocks or injections may be helpful.
SPG Blocks
For frontal headache, blocking the SPG can be helpful. This has been done for 100 years, but three newer devices make it easy to do. These are the SphenoCath, the Tx360, and the Allevio SPG device. Each of these shrinks the time required from1 h to a few minutes. SPG blocks, usually performed with bupivacaine, are safe, with few reported adverse events. For (frontal) CMs, the blocks are helpful if done 2 (or 3) days per week for several weeks.
Cervical Blocks/Injections
Various cervical procedures may be helpful, particularly if cervicogenic headache is present. When the pain is primarily in the posterior occipital area, and/or the neck, these procedures may be beneficial. Cervical epidurals may provide temporary relief. Facet injections often are useful as well. If the temporary blocks help, then procedures that are longer lasting might be more beneficial.
Occipital Nerve Blocks
For posterior head pain, blocking one or both occipital nerves may help, at least for a period of time. Occipital blocks are the treatment of choice when occipital neuralgia is present. If the pain is anterior and posterior, combining SPG and occipital blocks may provide relief.
Polypharmacy
Rational polypharmacy is commonly used for RCM. Comorbidities influence medications selection. Two (or more) preventives may be more effective than one. However, we also strive to minimize the number of medications used. If a patient is hypertensive and depressed, an angiotensin-receptor blocker plus an antidepressant might lessen the headache. Weight gain often is a concern, and with these patients, we avoid certain medications (valproate, amitriptyline, propranolol, etc.). Many RCM patients complain of being chronically tired. A number of headache medications may exacerbate fatigue. For patients with IBS, we would attempt to choose medications that may help treat the IBS and the headache. Some medications may help the diarrhea of IBS, but constipation tends to be a difficult problem in patients with IBS and headache because a number of headache drugs exacerbate constipation. Unfortunately, there are no algorithms that apply to complicated RCM patients. Each patient, with their comorbidities, is unique.
Miscellaneous
Methylergonovine (Methergine) is a smooth muscle constrictor that primarily is used to stop bleeding after childbirth. Methylergonovine is useful for a small number of RCM patients. The usual dose is one tablet three times daily. Triptans usually are not used concurrently. Availability has been a problem.
Muscle relaxants occasionally help those with RCM. We usually stick with nonaddicting muscle relaxants, such as baclofen (Lioresal) or cyclobenzaprine (Flexeril, Amrix). Fatigue is a common side effect. Another muscle relaxant, metaxalone (Skelaxin), minimizes fatigue. These agents may be beneficial for treating insomnia as well. Many patients use low doses of these (half a tablet at a time).
Memantine (Namenda) is a drug used for the treatment of Alzheimer’s disease and dementia. Memantine is an N-methyl-d-aspartate receptor antagonist that may be helpful for pain management. Memantine is a safe, well-tolerated drug. The usual dose of memantine is 14–21 mg per day.
New Developments
New approaches, such as transcranial magnetic stimulation (TMS), are becoming available. In December 2013, the US FDA approved the first TMS device specifically for the management of migraine (Cerena, eNeura TMS). According to the FDA, nearly 38 % of subjects who used the Cerena (eNeura) TMS when they had migraine pain were pain-free 2 h after using the device compared to about 17 % of patients in the control group. After 24 h, nearly 34 % of the Cerena (eNeura) TMS users were pain-free compared to 10 % in the control group [26]. TMS has few side effects and has been in testing for 10 years. Patients can have a unit at home that delivers several quick, magnetic pulses to the occipital cortex in the brain. Over time, we will see how effective TMS is for severe headaches. Studies are very promising.
Occipital nerve stimulation has been beneficial for a small number of RCM patients. Techniques of implantation have improved, but the technical challenges need to be overcome. The leads tend to migrate away from the occipital nerve , for example. While it is invasive, expensive, and associated with frequent side effects, nerve stimulation is viable for a small number of patients. Other nerves (such as the supraorbital) have also been the target of nerve stimulation.
In pharmacotherapy, there are a number of emerging compounds that may eventually come to market. These include newer preventive techniques, such as a monthly injection of a CGRP antibody. CGRP preventives are very promising.
Conclusion
RCM often is a disabling and debilitating illness. We face major challenges in attempting to define RCM. The definition must allow for severity of illness; also, degrees of refractoriness may change over time.
Other major areas of study within RCM include pathophysiologic mechanisms, the role of medication overuse, a search for biomarkers, psychological comorbidities, nonmedication approaches, and pharmacotherapy.
Patients with RCM who have MOH or psychological comorbidities require a combination of approaches. It “takes a village” to help those with severe, refractory headaches, and we need to guide the patient into comprehensive treatments. There are a number of viable therapeutic approaches, a number of approaches are presented in this chapter. However, we desperately need breakthrough medications and technologies that can prevent headache pain. Note this is an updated version of an article that appeared in the September 2014 issue of Practical Pain Management.
RCM: The Use of LAOs
Study results for a group of difficult-to-treat migraineurs provide a basis for determining efficacy and guidelines for the use of long-term opioids in this population.
Many patients with CM are refractory to our usual therapies [83]. Medication choices for the refractory chronic migraineur are limited and include polypharmacy with several preventives, MAOIs, botulinum toxin type A (Botox) and opioids, among others [67]. Each of these pharmacologic approaches helps a limited number of patients.
There have been a number of studies on LAOs as a treatment for refractory chronic daily headache [63, 87, 91]. Earlier studies focused on the use of low doses of methadone and a small minority of patients who did well in the long term. Several studies reported better success rates with other opioids, such as oxycodone CR or long-acting morphine preparations [66]. This suggested that, for the difficult-to-treat patient , this approach may be worthwhile, despite the difficulties in prescribing daily opioids.
The current study evaluated LAOs for those who had done well with SAOs for an extended period. These patients had been prescribed SAOs for significant periods in the past. Certain comorbidities were evaluated to assess if they could have predictive value as to who would do well with the opioid and who would fail. These comorbidities were also used to assess risk for abuse.
Study Design
This retrospective study was conducted at a single US headache clinic. Data were collected via chart review, patient diary, and patient interview. Patients who had been prescribed LAOs during the 6-year period 2002–2007 were assessed.
Patients kept a headache diary and used a ten-point visual analog scale to measure severity. Functional status was assessed with each visit. If adequate functioning was not maintained, the patient was usually withdrawn from the opioid. During each visit, the following were assessed in addition to functioning:
Pain level
Brief physical exam
Side effects of the opioid
Overuse/abuse behaviors
Patient Characteristics
For the study 115 patients were evaluated (87 female, 28 male, age range 23–77). All patients had been diagnosed as having RCM [96]. They had longstanding daily headaches that caused significant functional impairment or decreased QOL. Each patient had failed multiple trials of preventive medicines. In addition, they had little or no relief from abortive medications (triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), dihydroergotamine (DHE), etc.) While attempts were made to minimize MOH , patients with this condition were not excluded from using the LAOs. Virtually every one of these patients would qualify as RCM utilizing the 2008 proposed criteria for definition of refractory migraine and RCM [96].
Inclusion Criteria
Long-time patients at the treating headache clinic with a diagnosis of RCM were included. CM was defined according to the International Headache Society (HIS) criteria [100]. All patients had been prescribed LAOs, including methadone, long-acting forms of morphine or oxycodone, or the fentanyl patch during the years 2002–2007. All patients had previously shown improved functioning and QOL on SAOs. The minimum period of use of the SAOs was 1 year. Thirty-two (28 %) of the patients had abused the SAOs to some degree.
Primary Outcome Measure: Efficacy
The primary outcome measure was efficacy of the opioid. Efficacy was determined to be positive (+) if the patient continued on the LAO for at least 9 months and the patient consistently reported a 30 % or greater improvement in headache frequency and/or severity over baseline. The baseline of comparison was the 3-month period prior to initiation of the LAO.
Secondary Outcome Measures: Definitions and Criteria
Opioid Abuse
The term “opioid abuse” is not well-defined in the literature and is rather imprecise. However, we use this term for the study because it encompasses not only true addiction but lesser forms of overuse as well—such as chemical coping [56]. In our current study, patients were labeled as abusers if certain behaviors were severe, persistent, or pervasive. Some of the criteria were felt to be more significant than others. The criteria that we used included: early refill requests; dose escalations; insistence on increasing doses; abusive treatment of the staff regarding refills; false reports of stolen or lost medications; utilizing the opioid for depression or anxiety; using the opioid for other pains not discussed with the physician; receiving similar medication from other physicians; unexpected or abnormal urine screening test results; using illicit drugs or alcohol; repeatedly missing, canceling, or refusing appointments; selling the drugs; obtaining opioids from nonmedical arenas; frequent ER visits for opioids; hoarding, forging, or altering scripts; borrowing or stealing similar medications from family and friends; physical signs of overuse or addiction; and calls to the physician from family members with concerns about patient overuse [141, 110].
Anxiety
Patients with anxiety disorders included those with generalized anxiety disorder, panic disorder, and OCD. Anxiety was assessed via patient interviews, histories, and the initial anxiety and psychiatric assessment forms. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria were utilized [4].
Depression
Unipolar depression and dysthymia were evaluated according to DSM-IV criteria. Patient interviews, histories, psychiatric assessment forms, Beck Depression Inventory, and the PHQ-9 (Patient Health Questionnaire Depression Module) were utilized [4].
The Bipolar Spectrum
Evaluation was accomplished by the following: (1) chart review, (2) Mood Disorder Questionnaire, (3) PHQ-9 (Patient Health Questionnaire Depression Module), and (4) interviews with patients and families.
Personality Disorders
The diagnosis of PD was done in accordance with DSM-IV criteria [4]. Patients with severe PDs were not placed on the opioids. Only patients deemed moderate to severe with PD psychopathology were included [78].
The PD characteristics were pervasive, longstanding, and influential in social and work functioning. The purpose of this was twofold: to identify patients at risk to themselves and their health care providers, and to exclude those with marginal PD diagnoses. Cluster A, B, and C PDs were included. The most prevalent were borderline, avoidant, dependent, and obsessive–compulsive.
Attention Deficit Disorder
Patients with ADHD were included along with ADD. DSM-IV criteria were utilized [4]. Assessment was done via patient interviews, histories, and the Adult Self-Report Scale (ASRS).
Exercise
Patients who exercised at least 20 min a day on average (140 min per week) were considered to be exercisers.
Coping
Patients were assessed by the treating neurologist as to coping skills. Patients on disability due to headache were regarded as low copers. Medium to high copers were active and continued to work or go to school despite the presence of refractory pain.
Working Patients
These patients continued to be employed 15 h per week or more, or worked full-time at home, with normal functioning.
Disabled Patients
These patients were on long-term disability, or were unable to function more than minimally due to the CM.
Fatigue
These patients had longstanding (greater than 6 months) chronic fatigue, or excessive daytime sleepiness. Other than the headache, fatigue and/or tiredness were a primary complaint.
Statistical Analysis
Descriptive statistics (percentages) were used to summarize demographics and outcomes. A Z-test for proportion analysis was utilized. To be significant at the 0.05 level, the Z had to be > 1.96. The Z-test was applied to groups with specific psychiatric diagnoses.
Results
n = 115 (87 female, 28 male, age range 23–77).
Overall Efficacy and Number of Years on the Opioid
Sixty-five percent of patients were positive responders and response rates by type of patient or comorbid condition is summarized in Table 2.7. At the time of the study, the average number of years on the opioid for the positive responders was 4.5 years. The range was 9 months to 13 years. Seventy-three percent of patients reported at least one adverse event due to the opioid. The most common adverse events noted were: constipation (54 %), fatigue or somnolence (29 %), and nausea (21 %). Efficacy with regard to number of years of headache prior to starting the opioid was as follows:
Table 2.7
Summary of results by patient type or comorbidity (n/r = not reported)
Group by patient type or comorbidity | % of total sample | % of group showing long-term positive results from opioids | % of group that qualified as opioid abusers |
|---|---|---|---|
Anxiety (including generalized anxiety disorder, panic disorder, and obsessive–compulsive disorder) | 67/115 (58) | 44/67 (66) | 19/67 (28) |
Depression (nonbipolar) | 76/115 (66) | 52/76 (68) | 21/76 (28) |
Bipolar depression | 16/115 (14) | 10/16 (63) | 5/16 (31) |
Personality disorders (PD) | 29/115 (25) | 10/29 (34) | 13/29 (45) |
Attention deficit disorder (ADD) | 20/115 (17) | 13/20 (65) | 6/20 (30) |
Exercisers | 43/115 (37) | 26/43 (60) | n/r |
Nonexercisers | 72/115 (63) | 42/72 (58) | n/r |
Low copers | 32/115 (27) | 16/32 (50) | 9/32 (28) |
Medium to high copers | 83/115 (72) | 63/83 (76) | 21/83 (25) |
Working patients | 75/115 (65) | 45/75 (60) | 20/75 (27) |
Disabled patients | 19/115 (17) | 12/19 (63) | 4/19 (21) |
Fatigue | 15/115 (13) | 10/15 (67) | n/r |
Three to fifteen years of headache prior to opioid: n = 37, 69 % positive response.
Sixteen or more years of headache prior to opioid: n = 78, 61 % positive response.
Overall rate of opioid abuse (as defined above) was n = 30/115 (26 % of patients) as compared with previous abuse of SAOs, n = 32/115 (28 %). Of the latter, 91 % went on to abuse the LAOs as well. Information on smoking was available for 72 patients. Of the 53 identified nonsmokers, the abuse rate was 9/53 (17 %) while for the 19 who had smoked at some point, the abuse rate was 4/19 (21 %).
Statistical Analysis of Efficacy Rates
The rate of “positive efficacy” was compared to the rate of “no efficacy” for each of the following groups: those with anxiety, depression, bipolar depression, and PDs. A Z-test was utilized. To be significant at the 0.05 level, the Z had to be > 1.96. There were no significant differences for any of the above diagnoses between those who had a “positive efficacy” outcome versus those with “no efficacy:”
Patients with an increased chance of success included younger patients, high copers, and those without previous opioid abuse. Predicators of failure were those with personality disorders, older patients and, in particular, those with previous abuse of the short-acting opioids.
Discussion
We assessed 115 patients with RCM who were treated with LAOs during a 6-year period. This was a select group of patients who had all done well previously with SAOs. All of the patients in this study had already been on SAOs for at least a year.
Sixty-five percent of the patients did well for at least 9 months on the opioid. The average duration of use of the opioid was 4.5 years. Forty-four percent of the patients reported adverse events. Patients with an increased chance of success included younger patients, high copers, and those without previous opioid abuse. Predicators of failure were those with PDs, older patients and, in particular, those with previous abuse of the SAOs. In this study, anxiety, depression, bipolar depression, ADD, exercise, working, disability, fatigue, or cigarette smoking did not significantly change the long-term outcome.
Previous Studies
In one of our previous studies conducted in 1999 [65], a significantly lower rate of success (13 %) was obtained compared to the current study (65 %). This was, in part, due to an altered standard of success utilized in the current study. The current study defined success as a 30 % or more improvement in headache, compared to the 50 % in the previous study. In addition, patient selection has been greatly improved. For this study, every patient selected had demonstrated a favorable response to SAOs. Also, while 29 of these 115 (25 %) patients did have a PD, patients with severe PDs were not placed on opioids during this study period. This study ran from 2002 through 2007. I believe that our patient selection has steadily improved over the years, particularly in selecting those who have had success from SAOs without overuse and in not prescribing the opioids to those with severe PDs or other severe psychiatric problems.
In 1997, Saper and associates assessed refractory chronic daily headache with scheduled LAOs, particularly methadone [91]. There was a small subset of patients who did well. Similar results were obtained from Rothrock [87] and from Robbins [65]. Subsequently, Saper and his associates soured on the use of the opioids. An unpublished study from Rothrock indicated that in the CM patients who were responsive at 2 months to the methadone treatment, more than 70 % continued to maintain a response at 1 year [88]. Rothrock found that patients tend to either respond to relatively low doses or not respond at all. His studies also indicated that virtually all of the positive responders, when tapered off of the methadone, did relapse into their frequent headache patterns [88].
Saper found that only 10–15 % of initially enrolled patients experienced sustained, long-term, and meaningful improvement. Another meta-analysis of long-term efficacy with the opioids in more than 3000 patients resulted in the conclusion that there was no great evidence for sustained, long-term results in the majority of the patients [102]. In this, as in the majority of studies, there has been a high dropout rate due to adverse events and lack of pain relief.
Since 1870, opioids have gone through cycles of being overprescribed and underprescribed [36]. A balanced approach is probably best. Portenoy has stated that “There appears to be a select subpopulation of patients with chronic pain that can achieve sustained partial analgesia from opioid therapy without the occurrence of intolerable side effects or the development of aberrant drug-related behaviors [57].” In general, at least half of the patients who are prescribed opioids abandon them due to side effects or lack of efficacy.
Kalso analyzed 15 placebo-controlled studies involving 1145 patients for chronic, noncancer pain. Across all of the trials, the mean decrease in pain intensity was at least 30 % [38]. The vast majority (80 % of patients) suffered at least one adverse event. Constipation occurred in 41 % of patients, nausea in 32 %, and somnolence in 29 %. Fifty-six percent of the patients stopped the opioids due to lack of efficacy and/or side effects while 44 % continued in the long term. In various studies, the effects of opioids on QOL are inconsistent. Long-term, large, multicenter trials have not been done.
In one neurology office, Watson assessed 102 patients and concluded that opioids prescribed by the neurologist for chronic pain did lead to acceptable pain relief and decreased disability [108]. In a review of multiple randomized clinical trials, Farrar concluded that approximately a 30 % decrease in pain is the demarcation where most patients feel that it is relevant clinically [23]. Opioids have been tested versus tricyclic antidepressants (TCA) in several trials, and have generally proven somewhat more effective [102]. In one study in 2002, 54 % preferred the opioids versus 30 % the TCAs [59].
SAOs Versus LAOs
Short acting generally refers to not only how long a drug carries the desired effect but also the speed of the onset of the drug and how fast it drops off toward the end of the dose. Quick onsets and fast drop-offs are major determinants for abuse [36]. SAOs are not necessarily quick-onset medications. Most oral SAO tablets are slow to take effect. A short duration of action then leads to frequent administration and overuse may occur. However, it has not been proven conclusively in studies that SAOs lead to less or more abuse or are more dangerous than LAOs.
In a previous study by Doley, 81 % of self-selected patients on SAOs had continued good efficacy with the same dose, averaging four tablets per day of 7.5 or 10 mg hydrocodone. Eighty-one percent did say that the opioid was just as effective as in the previous month, and stable dosing was noted in these patients for an average of 31 months. Seventy percent of the patients remained free of any overuse violations or infractions. In addition, the patients on the SAOs had an increased QOL [20]. Self-selected groups, such as in our current study here, will report better efficacy because all patients who were chosen did well on the SAOs.
Although certain drugs—such as oxycodone CR—are more easily abused, it is the person, not the drug, who governs abuse. While some abusers have only one drug of choice, many will tend to abuse a succession of drugs.
Advantages and Disadvantages of LAOs
Several previous studies have evaluated daily opioids for severe chronic daily headache [63, 87, 91]. While success rates have been relatively low, they represent patients who have failed the usual ministrations, and who have few options available.
The advantages of LAOs include:
Avoidance of the “end-of-the-dose” phenomenon, with mini-withdrawals throughout the day
Consistent dosing one or two times daily, which decreases obsession with the next dose
Maintenance of stable blood levels
Avoidance of the acetaminophen, aspirin and NSAIDs that are included in many short-acting preparations
Probable diminished risk of significant abuse
Better compliance, with less psychological dependency on the drug
Disadvantages of LAOs include:
Social stigma
Fatigue and constipation
Difficulty in obtaining scripts, with no refills available
Need for frequent office visits and monitoring
Risk of OIH
Risk of abuse, although probably less than the SAOs
Interactions with other sedating drugs or alcohol
Risk of overdose
LAOs and Abuse
Most opioid abuse is secondary to immediate-acting opioids or the longer-acting ones that are easily convertible to short-acting ones. An example of this would be oxycodone CR. Younger people, particularly older adolescents, are the most frequent abusers [110].
Since their introduction in 1982, the LAOs have not been shown to be widely abused. The transdermal fentanyl has been available since 1991, and has only been minimally abused. It does not have a quick onset of action. Oxycodone CR (Oxycontin) has greatly increased the abuse rate, possibly owing to its hydrophilic nature where crushing it leads to a very quick onset. The newer abuse-deterrent preparations have been of some (limited) help in curbing abuse. Most of the abuse of LAOs is ingesting multiple oral tablets, often along with alcohol. Crushing and snorting or shooting the opioids is not as prevalent as oral ingestion. Despite the inherent problems, there has been an increasing use of continuous slow-release preparations for chronic pain [2].
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