A Dose of Truth about the Consequences of Opiophobia

The treatment of intractable pain remains an unresolved controversy in American medicine. Although, in theory, it is generally accepted that pain must be adequately treated, particularly in cancer patients, the treatment of pain unrelated to malignancy remains a stubborn and highly contentious issue.

As this decade has progressed, some legal experts assumed that as a consequence of certain tort actions (cf. Bergman v. Chin), physicians would be compelled to treat pain effectively in compliance with the community standard of care. In this civil lawsuit filed in San Francisco, CA, a jury found Dr. Wing Chin to be negligent in failing to adequately treat and relieve the suffering of his cancer patient, Mr. Bergman, and awarded Bergman’s family $2.5 million (reduced subsequently by the court to $1.5 million). According to the American Medical Directors Association, it was capped at $250K, then later upped to $375K.

In fact, Bergman v. Chin had little impact on the medical community. Not only has there been no subsequent case of its sort, there has been only a single instance in the US of a physician being disciplined by a state medical board for inadequately treating pain. In contrast, “unnecessary prescription of opioids” continues to be one of the most common causes of action taken against physicians who provide treatment for chronic pain unrelated to cancer.

Indeed, the case against pain management has been intensified in recent years. Insurance companies, clearly responding to the expense of pain medications, have attempted to deter pain treatment through filing state medical board complaints against doctors for “unnecessary prescribing." Insurers have also utilized the device of “peer-reviews” to discourage prescribing (described by some observers as “sham reviews”). Physicians (typically “interventionalists”) have been hired by insurers to opine that the prescriptions of opioids were “outside the standard of care,” claiming that only interventions conform to the standard of care and that the prescribing of opioids is unnecessary, excessive, dangerous, or addicting. Often, they recommend detoxification, denying or ignoring the medical necessity for ongoing treatment of intractable pain. Interestingly, when these “peer-reviews” are appealed to independent reviewers, affirmation of opioid treatment has been virtually universal.

An additional strategy in the campaign to save “opiophobia” from extinction has been a movement to establish arbitrary ceiling doses for opioid usage. One of the most egregious examples of this was the drafting of an arbitrary daily limit of 120mg of morphine, or its equivalent, in the State of Washington, which resulted in a federal lawsuit.

In my opinion, the justifications for limiting the use of opioid medications are exemplified in, and in many ways can be traced to, the article “Opioid Therapy for Chronic Pain,” by Jane C. Ballantyne, MD, and Jianren Mao, MD, PhD, published in the New England Journal of Medicine in 2003. There is no other peer-reviewed article in the medical literature promoting absolute or arbitrary limits on the use of opioids. The article has been frequently cited by anti-opioid activists.

Current Practice, a Disconnect In the article, Ballantyne and Mao noted that although many experts on pain recommend that patients suffering from chronic pain not be denied opioids, many physicians “remain uncertain about prescribing opioids to treat chronic pain and do not prescribe them.” The authors also noted that some (perhaps a minority) of pain practitioners think that “opioids are only marginally useful in the treatment of chronic pain, have a minimal effect on functioning, and may even worsen the outcome.”

This despite the fact that “key organizations that strongly support the use of opioids to treat chronic pain have published consensus statements to guide physicians in prescribing these drugs.” In their review of current clinical studies, Ballantyne and Mao stated that the opioid treatment literature was based mainly on “reports of surveys and uncontrolled case series,” and supported the view that patients with chronic pain can “achieve satisfactory analgesia by using a stable (nonescalating) dose of opioids, with a minimal risk of addiction.” Although the evidence shows that cognitive function is preserved in patients taking “stable, moderate doses of opioids for chronic pain,” patients may be impaired for several days following an increase in dose. The effect of high doses of opioids on cognitive function is “unknown.” Ballantyne and Mao went on to cite evidence showing that various pain syndromes, including neuropathic pain, are responsive to opioid therapy; that opioids are effective in the treatment of neuropathic pain; that long-term oral opioid therapy is useful for treating chronic pain; and that opioids can relieve pain even without functional improvement.

The authors stated that “pain relief is the expected end point of opioid therapy,” and that one of the “fundamental principles of pain management is that the dose of an opioid should be increased until maximal analgesia is achieved with minimal side effects.”

The authors noted that their clinical experience “suggests that many physicians take a much more liberal approach to dose increases,” with some patients receiving 1g or more of morphine or morphine equivalent per day, despite the availability of anecdotal evidence that suggests that “patients receiving opioid doses of this magnitude rarely report satisfactory analgesia or improved function.” They also note that “although the clinical trials carried out to date have not examined the efficacy and safety of prolonged, high-dose opioid therapy, evidence is rapidly accumulating that, in the treatment of patients with chronic pain, opioid doses should be limited in order to maintain both efficacy and safety.”

They support this assertion by examining the evidence surrounding the mechanisms of opioid tolerance and opioid-induced abnormal pain sensitivity, hormonal changes, and immune modulation. Ballantyne and Mao claim that long-term use of opioids may be associated with the development of abnormal sensitivity to pain (hyperalgesia). They also discuss how repeated administration of opioids not only results in the development of tolerance (a desensitization process), but also leads to a pro-nociceptive (sensitization) process, contributing to an apparent decrease in analgesia, pharmacologic opioid tolerance, increased sensitivity to pain, and/or the need for dose escalation.

Interestingly, they point out that it is unclear whether “opioid-induced abnormal pain sensitivity” is related to the dose, the particular opioid, the route of administration, the duration of use, or other factors. Nevertheless, the authors state, “abnormal pain sensitivity may, at least in part, explain the failure to relieve pain in some patients, despite increases in the opioid dose. Thus, in some instances, treating increasing pain with increasing doses of opioids may be futile.” Prolonged therapy with high doses of opioid medications, in addition to leading to adverse consequences such as opioid tolerance with the need for dose escalation and opioid-induced abnormal pain sensitivity, may, according to the authors, “increase the burden of care, because the management of opioid therapy in patients with complex problems is time-consuming and difficult.”

From these perceived dangers and limitations, the authors conclude that it may be proper to limit the dose of opioid medications in patients with complex problems. Thus, the concept of a “ceiling dose,” the acceptance of which is growing in clinical practice, say the authors, despite the fact that it is “difficult to define a dose that could be recommended as a ceiling.”

Certainty and Pain from Conjecture The Ballantyne and Mao article is now used by both individual practitioners and government authorities as a basis for attempting to set arbitrary and absolute limits on the dosage of opioids in managing intractable pain. However, in my opinion, a careful reading of their article reveals it to be largely conjectural, though subtly so.

Initially, they establish that the treatment of intractable pain is supported by the contemporary standard of medical practice. They then review the accepted approach to pain management through careful titration. Having established this foundation, they then proceed to construct their case against opioids, based upon the allegation that opioids may impair cognitive and personal function and the immune system; may cause serious hormonal problems; and may induce tolerance and allodynia and other pain hypersensitivities—giving the ultimate impression that opioids are ineffective except in narrowly defined circumstances.

Careful reading reveals that none of these allegations are supported by the medical and scientific literature they cite. Instead, every allegation is qualified with the statement that a given hypothetical adverse consequence of high and/or long-term opioid usage may manifest. Evidence that “suggests” something does not prove it; hypotheses are not conclusions. Indeed, the vast body of clinical evidence, to date, disproves the allegations.

The authors conclude their article by stating that “Whereas it was previously thought that unlimited dose escalation was at least safe, evidence now suggests that prolonged, high-dose opioid therapy may be neither safe nor effective. It is therefore important that physicians make every effort to control indiscriminate prescribing, even when they are under pressure by patients to increase the dose of opioids.”

I know of no publication, article, or practitioner that has ever called for the indiscriminate prescription of opioids. This is simply a straw man. But, most importantly, the hypotheses of adverse consequences—initially qualified and hedged through the use of terms such as “may,” “can,” and “could”—are thereby reified, giving the perception that opioids are over-prescribed, and that high doses are dangerous and must be limited, as they are neither safe nor effective. No evidence is offered to support any of these claims, and they are, in fact, scientifically indefensible.

The Ballantyne and Mao article does not establish that substantial evidence exists that high-dose opioid therapy is neither safe nor effective. In fact, there is no such evidence. Indeed, extensive clinical experience demonstrates that, in the treatment of chronic pain, opioids do not impair cognitive and personal function or the immune system (except in a limited number of instances of suppressed testosterone levels in males; opioids do not otherwise cause serious hormonal problems). High-dose opioids do not induce tolerance in intractable pain patients, nor do they induce hypothetical allodynia or other pain hypersensitivities to any significant extent. Opioids are effective in controlling pain and dramatically improving the quality of life in patients who experience chronic pain. Opioid overdoses are nearly always due to addictive misuse or unauthorized polypharmacy, frequently including alcohol, and are statistically insignificant among pain patients when the medication is used as prescribed.

Caution vs. Ideology

While it is judicious to exercise caution and continuing evaluation of the effects of long-term treatment of pain with opioids, the speculation that one may encounter adverse long-term effects is not a defensible basis for assuming that they do. The conclusions reached by Ballantyne and Mao are not supported by any substantial or factual evidence. Indeed, the preponderance of actual evidence and clinical reports conclude the opposite. To date, none of the assertions presented in the article have been backed by substantial or reproducible supporting evidence. Sadly, the information and opinions in this article have been widely circulated and repeated, with many physicians uncritically quoting the hypothesis of hyperalgesia as an accepted fact, despite the lack of a single citation in the medical literature of a peer-reviewed article, based upon scientifically defensible evidence, supporting this theory. Caution is laudable in the practice of medicine. Ideology, masquerading as a scientifically objective review of the literature, is not.

Joel S. Hochman, MD, is the executive director of the National Foundation for the Treatment of Pain.

“Hyperalgesia… is used in two different contexts in pain medicine. In one context, hyperalgesia refers to the excessive pain often induced by neuropathies or certain chemicals… Another context is the unfounded assertion that some patients who chronically take high-dose opioids develop increased pain with increased doses, or increased sensitivity to noxious stimuli. This is based on studies of laboratory animals, and of people given intrathecal opioids or studied under other unusual conditions. I am unaware of any studies supporting the existence of this phenomenon in clinical practice with respect to patients chronically on oral or transdermal opioids. The assertion of opioid-induced hyperalgesia has found its greatest usefulness by physicians and regulators looking for justification to limit opioid prescribing, and by some cost-conscious insurance companies seeking a medical reason to deny payment for high doses of opioids.”

Jennifer Schneider, MD, PhD, from a guest editorial that appeared in the Jan/Feb 2009 issue of Practical Pain Management.