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Long-Acting Opioids for Severe Chronic Daily Headache (Posted April 2001)
Sustained-release Morphine Sulfate (Kadian) for Severe Chronic Daily Headache - abstract (Posted Feb 2001)
Long-term scheduled opioid treatment for intractable headache: 3-year outcome report (Posted Nov 2000)
Chronic Methadone Therapy for Refractory Pervasive Primary Headache (Posted June 2000)
Long-Acting Opioids as Preventive Medicine for Severe Headaches (Posted May 2000)
Long-Acting Opioids for Severe, Refractive Chronic Daily Headache: Sustained- Release Morphine, Methadone, and Controlled-Release Oxycodone (Posted March 2000)
Sustained-Release Morphine Sulfate For Severe Chronic Daily Headache (Posted Feb 2000)
Long-Acting Opioids for Severe Chronic Daily Headache (Posted June 1999)
Opioids for Noncancer Pain: from Controversy to Consensus (Posted Nov 1998)

Chronic Methadone Therapy for Refractory Pervasive Primary Headache

To determine the utility of chronic methadone therapy for patients with pervasive primary headache previously refractory to treatment with conventional prophylactic agents.

Patients with frequent episodic migraine (FEM) or chronic daily headache (CDH) consecutively were evaluated at a university-based headache clinic and screened for their potential participation in a study involving chronic treatment with methadone according to a standardized dosing regimen. A positive treatment response was defined as a 50% or greater reduction in headache days per month relative to baseline headache frequency.

Thirty patients were enrolled, of whom 5 had FEM and 25 had CDH. Twenty-seven (90%) were female, and mean age for the entire group was 46.6 (range 29-70). Mean number of prophylactic agents previously tried was 6.2 (range:3-10). Of the CDH patients, there were 17 with transformed migraine and 8 with new daily persistent headache with migrainous features; duration of CDH ranged from 2 months to 30 years and exceeded one year in 16 (64%). Ten patients (33%) stopped treatment due to side effects, of which nausea was the most common (cited by 7/10). Twenty patients (67%) completed the methadone dose escalation schedule, and 12 of them (60%) achieved a positive treatment response; all but one required the maximum target dose (30 mg. daily) to obtain satisfactory and sustained relief. Patient age, CDH subtype, total duration of daily headache and extent of prior prophylactic therapy did not predict treatment response. Mean duration of methadone treatment for responders was 21.9 months (range: 6-48 months). Three of the 12 responders (25%) developed methadone tolerance/headache recurrence, and one of them improved following dose increase. Of 5 responders who attempted to stop methadone after an extended period of successful headache control, all experienced rapid recurrence of headache and resumed treatment. Of the 30 patients enrolled, one (3%) exhibited evidence of methadone abuse, and no patient was noted to overuse other analgesic medication. Overall 7 of 30 patients (23%) achieved and chronically maintained a positive treatment response.

In a significant minority of patients with refractory pervasive headache, chronic methadone therapy will be well tolerated and effective.

Opioids for Noncancer pain: from Controversy to Consensus
by Alan Spanos, MD

The following is an excerpt from a modified version of the article that first appeared in the International Journal of Pharmaceutical Compounding, 2(2): 106-108, 1998.

Over the last decade, a controversy over the use of opioids for chronic noncancer pain has evolved towards a consensus. the previous position was that opioids should only be used for acute, severe pain and for cancer. Their use in chronic, noncancer pain was regarded as both useless and dangerous, and physicians prescribing in such cases were commonly investigated by their state medical boards or the Drug Enforcement Administration. This position was based on three opinions: first, that patients maintained on opioids commonly developed addiction; second, that tolerance rapidly developed so that opioids were then useless even for acute pain in emergencies; and third, that opioids had medically dangerous side effects such as respiratory depression and liver damage.

If these opinion are true, they would certainly be strong reasons for avoiding opioids in chronic noncancer pain. However, evidence has accumulated that each of them is false. The result is that many senior pain specialists now acknowledge that we have been withholding our strongest, safest, pain medications from countless people whose pain could be substantially and permanently relieved...

...The first misconception, that of addiction being caused by medical use of opioids, has been dispelled by several large studies.1,2,3 In one of these, addiction was looked for in 10,000 patients who had been treated for extensive burns, requiring prolonged use of opioids in hospitals. Not a single case of iatrogenic (due to treatment with opioids) addiction was found.2 ....

...As for tolerance, this is much less common than used to be believed. Moreover, when it does occur, it is only partial: the opioid dose may have to be increased moderately, but opioid sensitivity remains at the higher dose. Most cases of apparent tolerance to opioid analgesia have actually represented progression of the pain condition for which they were prescribed. The increased "nocioceptive load" therefore required a higher dose of opioid to counteract it. Interestingly though, although tolerance to analgesia is not a great problem with opioids, tolerance to the side effects of sedation and nausea usually happens within a few days. Even the constipation so routinely induced by opioids does often diminish with time, though this may take many weeks or even months.

The third misconception was about medical adverse effects of opioids. Respiratory depression is the major fear, based on experience with parenteral (intravenous, intramuscular, subcutaneous) opioids. But it is not seen with opioids titrated (determining proper dose to alleviate pain) orally. As for liver damage, this is a misconception: opioids do not do this. The mistake arose because so many opioid preparations also contain acetaminophen, which is of course highly hepatotoxic (damaging to the liver) in overdose...

...Despite these ingrained misconceptions, many doctors have learned from experience that opioids are much safer, and much more effective , than they have been taught. Their experience is now validated in the position paper of the American Pain Society and the American Academy of Pain Medicine. These organizations hold that opioid treatment for selected cases of chronic noncancer pain is now the standard of care. It follows that to refuse to consider such treatment as an option is now unorthodox. Physicians who withhold opioids "on principle" from patients with chronic pain are condemning countless people to lives of unremitting but unnecessary agony. It is nothing short of scandalous that many pain clinics still refuse to include long term opioid therapy among their options. They should be required to tell their patients that their practice is "unorthodox" according to the pain specialists' own authorities. And physicians who do use long term opioid therapy should feel reassured that their practice is now supported by expert consensus.


  1. Melzack R. The Trajedy of Needless Pain. Scientific American 262 (2): 27-33, 1990.
  2. Porter J and Hick H: Addiction rare in patients treated with narcotics. N Engl J Med 302:123, 1980.
  3. Perry S and Heidrich G: Management of pain during debridement: A survey of U.S. burn units. Pain 13:267-280, 1982.

Long-term scheduled opioid treatment for intractable headache: 3-year outcome report
A.E.Lake,III, Cephalalgia, May 2000

To assess long-term efficacy of a scheduled opioid program.

Although 68% of those remaining on scheduled opioids for three years improved > 50%, this was only 31% of those initially entered. Despite dose titration and trials of alternative opioids, patients were generally either good or poor responders from the start. Schedule opioids have a limited place in headache treatment, but can significantly help a select few.