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Patients Who Require Ultra-high Opioid Doses

The goal of ultra-high dosage therapy is to relieve pain and improve function in those chronic pain patients that are profoundly ill, impaired, and/or bed- or house-bound, without producing sedation.
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Mrs. J, a 32-year-old woman, was pre-scribed methadone for severe headaches that resulted from a head injury sustained in a motor vehicle accident. Despite multiple increases in the dose, up to 200mg/day, she said the pain was barely diminished. Finally, a specialist ordered a serum methadone level, which came back extremely low. Further evaluation reveal-ed that Mrs. J was also taking Tegretol for a seizure disorder that had also resulted from the head injury. Tegretol is known to markedly increase the metabolism of methadone and explained the low serum methadone level. The patient was switched to a different opioid that proved to be much more effective.

A second reason to obtain a serum opioid level in patients on ultra high-dose opioids is to establish baseline serum levels that can be compared to future tests. It is unfortunate that when a patient who is on high-dose opioids suddenly dies and the cause of death is not immediately apparent, a medical examiner who finds high levels of opioids in the blood may conclude that the patient died of a drug overdose. Some physicians have found themselves accused of causing the patient’s death. A strong defense is a similar high opioid blood level documented in the patient’s record at a time when the patient was ambulatory and doing well. Serum opioid levels in patients on high-dose opioids have been published and have been used successfully in the defense of physicians.7

Hazards of Non-opioid Drugs

We highly recommend that patients who require ultra-high opioid dosage be restricted in their use of benzodiazepines, muscle relaxants and other sedatives. Although some use of these drugs may be necessary, they may produce drug interactions that may be hazardous. It is unclear as to why some patients require ultra-high opioid dosages but some, if not the majority, may have a cytochrome P450 or other genetic abnormality. This enhances the probability of drug interactions with opioids.8

Table 3. Some Basic Management Recommendations
  • Physical examination on admission and periodically thereafter
  • Review records of previous treatments
  • Family education
  • Monthly visits until stable
  • Screening for hormone abnormalities
  • Normalize blood pressure and pulse rate
  • Titrate dosage upward to maximize function without sedation
  • Urine screening for compliance, abuse or drugs

Management Recommendations

The initial evaluation must include a medical history, queries about the patient’s prior and present use of alcohol and other drugs, previous addiction history, physical exam, and baseline laboratory studies, among others (see Table 3). It is essential to obtain relevant old records. Goals and objectives should be established along with a discussion of what constitutes a realistic goal or objective for the specific patient. Some might include 30-50% pain relief, the elimination of bed- or house-bound days, cessation of emergency room visits, or resumption of regular eating and sleeping habits. There should be some emphasis and motivation to improve social interaction since many such patients have been house-bound for extended time periods. Part of this discussion should be to clarify to the patient that improved function is as important a goal as is pain relief. The patient needs to be actively committed to following through on the physician’s recommendations regarding physical therapy, exercise, and other measures to improve function. A regular monthly visit is highly recommended until the patient is stable. After that, some physicians are comfortable seeing the patient only every two, or even three, months as long as they remain stable. Family attendance is highly desirable in the first few visits. It is recognized that not everyone has a family, and not everyone with a family has a member who agrees to accompany the patient.

At each follow-up visit, at a minimum, the 4A’s as advocated by Passik and colleagues, should be assessed and documented in the patient’s chart.9 These comprise:

  • Analgesia. Ask about pain relief using a scale such as 1 to 10 or the Faces scale.
  • Activities. Assessment of the patient’s function, level of exercise, etc.
  • Adverse effects. Constipation and their bowel program; possible sedation; subnormal testosterone level and its treatment.
  • Aberrant. Drug-related behaviors such as early refills, evidence of non-compliance.

In addition, it’s desirable to include a fifth A for ‘Affect’ which comprises the patient’s mood. Chronic pain patients are often depressed since depression and pain reinforce each other. Depression may need to be treated with an antidepressant and possible referral for counseling, if indicated.

Ancillary Measures

We recommend a great emphasis be placed on movement and physical exercises. Other additions may include electrical measures (electric, microelectric, radio frequency, etc.), topical analgesics (e.g., lidocaine patch), hormone replacement, and resocialization counseling. Invariably, patients who require ultra-high opioid dosages have been too ill to carry on normal social or family functions. They usually have to be guided and motivated to resocialize and begin a new quality of life.

Successful surgery, such as total knee replacement or back fusion, significantly reduces pain and typically results in a decreased opioid dosage requirement. In general, however, there is no necessity to ever lower or cease opioid treatment if the patient’s pain and function are significantly improved and the patient is tolerating the medication well. A trial of gradual dose reduction may be attempted, but should not be a primary goal. As with other chronic diseases such as diabetes or schizophrenia, treatment may extend for the patient’s lifetime.

Search For Cause

It is unclear as to why some patients with seemingly no worse underlying cause of pain need an ultra-high dose while others don’t.2,6,8 We recommend physicians attempt to determine a possible reason for the ultra-high dose requirement. One of the authors has found that a good place to start is opioid serum levels.5 Very low levels relative to the dosage may indicate malabsorption or a genetic liver enzyme defect, while very high opioid serum levels may indicate a liver enzyme defect or some resistance at the blood brain barrier or opioid receptor sites. Malabsorption is common in patients with a gastrointestinal disorder, diabetes or abdominal surgery. One of the authors, as well as other researchers, have begun testing ultra-high dose opioid patients for cytochrome P450 abnormalities, and early evidence suggest that as many as one-third of ultra-high dose patients may have an abnormal genotype. Early testing suggests that high opioid serum levels may be required to make a “lazy” genotype do its job and metabolize opioids.8,10

Last updated on: December 20, 2011
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