Are Opioids Useful When Taken Prophylactically for Intractable Migraine?
Beginning in the 1990s, a dramatic increase in opioid treatment for non-terminal chronic pain conditions has been seen. This turnaround from a previously very hesitant approach to opioid prescribing by the medical community was largely fueled by pharmaceutical companies and a small group of investigators who asserted that fears of tolerance and addiction were exaggerated, and proselytized the daily use of opioid medications for painful illnesses including arthritis, back pain, fibromyalgia, and chronic headache disorders. Despite relatively sparse evidence for efficacy and safety, a nearly religious movement seemed to take hold, leading to the concepts of "Pain as the fifth vital sign" and that undertreatment with opioids was essentially unethical. Assessments of pain management programs nationally and internationally were predominantly assays of access to opioid-based treatment. A 2008 review discovered that of all long-term opioid therapy at that time, more than 90% was being prescribed for chronic non-cancer pain. Between 1997 and 2002, oxycodone prescriptions alone quadrupled and a 2009 study reported that more than 3% of all adults in the US were receiving long-term opioid therapy for chronic non-cancer pain. During the same period, opioid addiction and its consequences, including deaths from unintentional overdose, markedly increased. Between 1985 and 2005, data from the National Vital Statistics System of the Centers for Disease Control and Prevention show that the death rate from unintentional drug overdose increased by nearly 600%, much of this is due to prescription opioid abuse.
During the same roughly 20-year period, trends in treating patients with frequent headaches paralleled the dramatic rise in opioid use for non-malignant pain. Guidelines published by the American Pain Society in 2009 proposed chronic headache disorders as one of the 4 common chronic pain conditions where chronic opioid therapy might be considered. And a number of regimens for continuous opioid therapy have been devised for patients with refractory CM and other intractable chronic headache disorders ( Table 5 ). However, evidence for the effectiveness of chronic opioid treatment of CM patients is lacking. Saper et al have followed a large cohort of refractory headache patients treated with daily opioid therapy, and while initially promising, results have begun to look bleak. While about one quarter of the 160 enrolled patients seemed to attaining a 50% or better improvement (using an index of severe headache activity), other measures were much less encouraging, and there was serious question as to the validity of patients' self-reporting. Disability scores, for example, did not improve even for this group, and behaviors such as drug-seeking and dose violation seemed to persist for many. Other reports suggest better results for opioid therapy in headache, but all are fraught with a number of pitfalls. First, when comparing active and placebo responses, maintaining good blinding is probably impossible because of the euphoric and sedating properties of opioids. Related to this is the presumed tendency for patients to exaggerate improvement with opioids do to the anxiolytic and other beneficial effects on mood, not to mention the potential impact of habituation.
Adverse effects to opioids may be amplified when use is daily. Significant gastrointestinal dysfunction in particular has been seen in many patients on continuous opioid therapy. The "opioid bowel syndrome" can include intractable severe abdominal pain, which in some cases leads to inappropriate escalation of opioid medication. The most worrisome potential adverse effects from regular opioid use are respiratory depression and sudden cardiac death presumably because of arrhythmia. These potentially life-threatening phenomena are difficult to quantify but clearly exist. Methadone is particularly worrisome because of its long half-life (as long as 50 hours in some patients) with unnoticed rising blood levels. In addition, methadone is known to prolong the QT interval so can lead to fatal arrhythmia (torsade de pointes). Significant sleep disturbance and sexual dysfunction can also emerge in patients taking daily opioids. Webster et al studied 147 patients receiving daily opioids for various pain conditions and found sleep apnea in 75% (either obstructive or central).
Cognitive and behavioral function must be closely monitored in any patient on daily or even frequent opioid medication. Mood alteration, mental fogginess, and motivational issues are universally known side effects to opioids in humans. Some of these do lessen with tolerance, but symptoms of anxiety and mood change can lead to increased use. Sjogren et al in 2000 studied cognitive function in 40 patients receiving long-term oral opioid therapy for non-malignant pain, primarily sustained-release morphine or methadone, and compared psychometric performance with 40 age-matched healthy volunteers. Clear relative deficiencies in memory, attention, and psychomotor speed were found in patients on opioid therapy. However, other studies have not replicated these results. The obvious confounding issue in attempting to assess cognition and behavior is that any abnormal function in these areas might be the result of pain, anxiety, or depression because of the medical condition rather than the opioids themselves.
Along with the nearly inevitable tolerance to analgesic benefits that seems to accompany frequent opioid use, a seemingly paradoxical phenomenon – opioid induced hyperalgesia (OIH) – has been observed.
This has clearly been shown to occur in many patients taking daily opioids and is diagnosed clinically by noting increased pain despite an increase in dosage (which generally happens if the prescriber incorrectly assumes tolerance has developed). OIH, while not completely understood, probably results from a number of mechanisms including activation of excitatory anti-analgesic pathways, pain facilitation via dynorphin and CCK activation, increased activity of nociceptive pathway excitatory neuropeptides (calcitonin gene-related peptide and substance P), descending facilitation of pain involving the RVM and probably glial activation with release of cytokines that augment nociception. OIH can easily be misdiagnosed as tolerance or disease-worsening, but a clue can be local allodynia, in addition heightened pain with dosage increase.
Finally, as described earlier, MOH can compromise the potential benefits of opioids for relief of chronic headache disorders. With daily opioid use, presumably the risk of MOH rises significantly. While this is difficult to assess, several authors have demonstrated improvement in chronic primary headache following discontinuation of opioid medications.
Despite the many negatives, there will be selected cases for whom one could consider continuous opioid therapy. These might include patients who are truly refractory to a number of properly executed pharmacological and non-pharmacological approaches, or who truly cannot tolerate any of the alternatives. Saper and his team have devised a set of guidelines for choosing patients who might be appropriate for daily opioid therapy ( Table 6 ). These guidelines are based on data from longitudinal studies as well as years of accumulated experience in working with intractable patients and opioid programs. They stipulate that patients be over 30, have very frequent and disabling pain, and have a history of good compliance. They also require that the pain has been refractory or that typical measures are contraindicated, and that the patient is well known to the skilled prescriber. Past addictive disease, serious mental illness, inappropriate drug-seeking behavior, and a home environment that includes drug abuse are all considered contraindications to chronic opioid treatment. Formal monitoring including a thorough written contract, urine drug screening, and regular office visits including psychological counseling are all required.