Opiophobia is a Worldwide Tragedy
“The majority of (Australian) pain physicians support opioid medication use. The case against its use is largely dependent on a single flawed article (see Ballantyne et al below).
Despite the fact that the majority of pain physicians support the use of opioid medication, some practitioners and some governments have tried to limit its use. This decision is not based on any clinical or relevant research evidence. This decision has been based on prejudice and ignorance of proper opioid (treatment). At the base of this conduct is “opiophobia”.
The majority of reputable pain organizations, including the International Association for the study of pain (IASP) the largest pain organization representative group, and the International Association for Pain and Chemical Dependence ( IAPCD) support opioid medication, and recognize that in a some specific cases large doses of opioid medication are the preferred course of action.
Although there is debate about absolute or arbitrary limits on use of opioids, many conclusions proposed in the case against pain management are flawed (see Hochman below).
1. there is no evidence to support the claim that an upper limit of dosage should be mandated. (From a treatment perspective there is no evidence to show that there is ceiling dose, and as the dose increases, the analgesic benefit will also improve).
2. there is no evidence that these medications impair cognitive and personal function, indeed they frequently improve both.
3. addiction is uncommon.
4. the rationale to opioid use is purely relief of symptoms and improvement of function.
In South Australia there has been a major bureaucratic effort to obstruct and prevent treatment of chronic pain. This has been achieved by numerous measures: -
• improper denial of pain relief to patients.
• inappropriate action against practitioners administering to these patients.
• Treatment decisions made by administrators lacking the appropriate technical skills. (Not one patient has been examined by them).”
– Ian Buttfield MD,
Australia
“HYPERALGESIA”, “OPIOPHOBIA”. AND BALLANTYNE AND MAO: AN ANALYSIS
January 14, 2009
The treatment of Intractable Pain remains a peculiarly unresolved controversy in American medicine. Although, in theory, it is generally accepted that pain must be treated, particularly in cancer patients, the treatment of pain unrelated to malignancy remains a stubborn issue.
Some legal experts assumed that as a consequence of tort actions (Bergman v Chin) physicians would be forced to treat pain effectively in compliance with the community standard of care. In this civil lawsuit in San Francisco, California, a jury found Dr. Chin to be negligent in failing to
adequately treat and relieve the suffering of his cancer patient, Mr. Bergman, and awarded his family $2.5 million (reduced subsequently by the court to $1.5 million).
In fact, the Bergman v Chin case had little impact on the medical community. There has been no subsequent case of its sort. Further, in the entire United States, there has been only a single instance 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 daring to treat chronic pain unrelated to cancer.
Indeed, the case against pain management has been intensified.
• 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”.
o They falsely claim that only interventions conform to the standard of care; that the prescribing of opioids is “unnecessary”, “excessive”, “dangerous”, or “addicting”.
o They recommend detoxification, denying or ignoring the medical necessity for on-going 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 limits on opioid usage, reaching a recent zenith in the drafting of an arbitrary daily limit of 120 mg of morphine, or its equivalent, in the State of Washington (resulting in a federal lawsuit.)
The opioid limitation campaign has largely depended on a single article, by Ballantyne and Mao, published in the New England Journal of Medicine in 2003 (purportedly the product of peer review.) 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.
Given the central position of this article in the struggle around pain management, this author decided to revisit the original publication, to examine its content, assumptions and conclusions. The findings were enlightening.
BALLANTYNE AND MAO
Turning to the article, Ballantyne and Mao stated that:
1. Experts on pain recommend that pain patients not be denied opioids.
2. Despite this many physicians remain uncertain about prescribing opioids and do not prescribe.
3. Some physicians (a minority) argue that opioids are only marginally useful in the treatment of chronic pain, have a minimal effect on improving functioning, and may even worsen the outcome.
4. Key organizations strongly support the use of opioids to treat chronic pain and have published consensus statements to guide. Ballantyne and Mao reviewed the common elements in these guidelines, including regular assessment of the achievement of goals, careful monitoring for signs of opioid abuse (including toxicological screening in some cases), the use of adjunctive treatments whenever possible, and a willingness to end opioid treatment if the goals are not met, and full documentation.
Ballantyne and Mao then discussed clinical studies, noting that:
1. Most of the literature on opioid therapy consists of reports of surveys and uncontrolled case series and that patients with chronic pain not associated with a terminal disease can achieve satisfactory analgesia by using a stable (non-escalating) dose of opioids, with a minimal risk of addiction, in up to six years of treatment.
2. In most cases, doses are in a moderate range (up to 195 mg of morphine or morphine equivalent per day.
3. In other reports, higher doses were used (up to 2 g/day)
4. Some studies have also assessed functioning on the basis of patients’ own reports, with most patients reporting improvement.
5. Studies have shown that cognitive function, including the ability to drive and operate machinery, is preserved in patients taking stable, moderate doses of opioids for chronic pain.
6. However they then asserted that cognitive function may be impaired for up to seven days after an increase in the dose, “though the effect of high doses of opioids on cognitive function is unknown. “
7. Several controlled studies involving the use of single doses or short intravenous infusions of opioids confirm the responsiveness of various pain syndromes, including neuropathic pain.
8. Neuropathic pain has traditionally been considered opioid-resistant. However, recent clinical studies have shown opioids to be effective, provided an adequate dose can be reached without excess side effects.
9. Controlled studies have assessed the usefulness of long-term oral opioid therapy for chronic pain, and show significant analgesic efficacy of opioids in the treatment of chronic pain, including neuropathic pain,
10. The evidence of their effect on functioning is mixed, with a few studies reporting that pain relief was achieved without functional improvement.
11. Pain relief is the expected end point of opioid therapy, but there is no consensus on whether pain relief without other benefits is a reasonable outcome
12. A fundamental principle of pain management is that the dose of an opioid should be increased until maximal analgesia is achieved with minimal side effects.
However, despite their recognition of all these findings, Ballantyne and Mao then directed their focus on their view that dosage of opioids must be limited. They stated:
1. Clinical experience suggests that many physicians take a much more liberal approach to dose increases. Some patients with chronic pain receive doses as high as 1 g or more of morphine (or a morphine equivalent) per day, which may be five or more times the doses validated by the literature
2. Anecdotal evidence suggests that patients receiving opioid doses of this magnitude rarely report satisfactory analgesia or improved function.
3. 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.
4. Opioid Tolerance is an adaptive process at the cellular level
a. Several mechanisms are linked to the desensitization of opioid receptors
b. In patients receiving prolonged opioid therapy, increased expression of the endogenous opioid dynorphin has been noted in the spinal cord dorsal horn associated with enhanced pain sensitivity.
c. Although the exact mechanisms of NMDA-receptor–mediated opioid tolerance have not yet been elucidated, this line of research has provided insights into several issues related to prolonged opioid therapy.
d. Long-term use of opioids may also be associated with the development of abnormal sensitivity to pain
e. Preclinical and clinical studies suggest that opioid-induced abnormal pain sensitivity has much in common with the cellular mechanisms of neuropathic pain.
f. Animal models have also shown that NMDA-receptor–mediated cellular mechanisms mediate irreversible neurotoxic changes.
g. Repeated administration of opioids not only results in the development of tolerance (a desensitization process) but also leads to a pro-nociceptive (sensitization) process.
h. Together, desensitization and sensitization arising during prolonged opioid therapy may contribute to an apparent decrease in analgesia.
i. Prolonged opioid therapy can lead to cellular and intracellular changes,
j. Such changes may contribute to pharmacologic opioid tolerance, increased sensitivity to pain, or both and the need for dose escalation.
k. Prolonged opioid treatment may also result in hormonal changes and may alter immune function.
l. These effects may be exacerbated by dose escalation in some circumstances.
m. Thus, the need for dose escalation during opioid therapy — that is, the development of “apparent” opioid tolerance — may be the result of pharmacologic opioid tolerance, opioid-induced abnormal pain sensitivity, or disease progression.
n. Exogenous opioids may affect immunity through their neuroendocrine effects, or through direct effects on the immune system.
o. On the basis of studies in animals, prolonged exposure to opioids appears to be more likely to suppress immune function than short-term exposure, and abrupt withdrawal of opioids may also induce immune suppression.
p. Different opioids appear to act differently on the immune system. For example, methadone may be less immunosuppressive than morphine.
q. Studies of immune function in patients receiving long-term opioid therapy for chronic pain are notably lacking, but the direct evidence that opioids impair immune function has aroused concern, particularly in the case of susceptible persons. (However, pain itself can impair immune function)
r. The greatest concern is likely to pertain to patients receiving high doses of opioids who do not obtain satisfactory pain relief.
s. Apparent opioid tolerance does not equal pharmacologic opioid tolerance; and prolonged, high-dose opioid therapy may have serious adverse con-sequences.
5. Clinical tolerance is related to pharmacologic tolerance
a. Pharmacologic tolerance to opioids has defined cellular mechanisms.
b. Tolerance is the need for increasing doses to maintain the same level of analgesia.
c. There is evidence that opioids can induce abnormal pain sensitivity or hyperalgesia,
d. Although sophisticated testing can identify hyperalgesia (to distinguish it from pharmacologic tolerance), it may not distinguish the hyperalgesia due to opioid treatment from the hyperalgesia due to worsening neuropathic pain.
e. In every day clinical practice (without testing), it is impossible to distinguish between pharmacologic tolerance and abnormal pain sensitivity.
f. 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 remains unclear.
g. 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 in-creasing doses of opioids may be futile.
6. High dose opioid, prolonged, therapy opioids may have adverse consequences, including:
a. opioid tolerance with the need for dose escalation, and opioid-induced abnormal pain sensitivity.
b. hormonal effects that result in reduced fertility, libido, and drive.
c. immunosuppression, especially in susceptible persons. (“We do not yet know to what extent these effects are clinically relevant. However, prolonged use of high doses of opioids is likely to be more toxic than short-term use of low doses, so hormonal effects are most likely to occur in patients with chronic pain who receive high-dose opioid therapy”).
d. Paradoxically, opioid treatment may actually increase the burden of care, because the management of opioid therapy in patients with complex problems is time-consuming and difficult.
7. The concept of a ceiling dose of opioids in the treatment of chronic pain is growing, yet it is difficult to define a dose that could be recommended as a ceiling. Daily doses above 180 mg of morphine or a morphine equivalent have not been validated in clinical trials involving patients with chronic pain and might be considered excessive. However, ceiling doses probably vary among patients, given the known differences in patients’ responses to opioids. More important than the dose itself, however, may be the need for frequent dose escalation beyond the time when establishing a stable dose during the dose-adjustment phase (e.g., up to eight weeks) would be reasonable. The goal of these strategies is to maintain opioid efficacy while avoiding an adverse outcome.
8. 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.
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ANALYSIS
Drs. Ballantyne and Mao created a document which is now used, uncritically, by both individual practitioners and governmental authorities, as a basis for attempting to set arbitrary and absolute limits on the dosage of opioids in managing intractable pain. However, 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 attempt to construct their case against opioids.
Their case is based upon:
1. The allegation that opioids may impair cognitive and personal function
2. The allegation that opioids may impair the immune system
3. The allegation that opioids may cause serious hormonal problems
4. The allegation that high dose opioids may induce tolerance
5. The allegation that opioids are ineffective
6. The allegation that high dose opioids may induce allodynia and other pain hypersensitivities
Careful reading reveals that none of these allegations are supported by the medical and scientific literature they cite. Nowhere do they state that they do. Instead, every allegation is qualified with the statement that this hypothetical adverse consequence of high and/or long-term opioid usage may be so. Evidence that “suggests” something does not prove it. Hypotheses are not conclusions. They remain hypotheses until proven. None of these allegations have any basis in proof. Indeed, the vast body of clinical evidence, to date, disproves the allegations, with the single exception noted below.
Their clear objective was to construct an argument against opioids, under the rubric of a review of the medical literature.
“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.”
We know of no publication, article or practitioner who 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 by “may”, “can” and “could”, are suddenly reified, and a leap is made to an ideological absolutism. “Opioids are over-prescribed, 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 in fact 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, all clinical evidence points to the opposite conclusion.
Specifically, extensive clinical experience demonstrates that, in the treatment of chronic pain:
1. opioids do not impair cognitive and personal function
1. opioids do not impair the immune system (except in a limited number of instances of suppressed testosterone levels in males)
2. opioids do not cause serious hormonal problems, otherwise
3. high dose opioids do not induce tolerance (in intractable pain patients)
4. opioids are effective in controlling pain and dramatically improving the quality of life of pain patients
5. high dose opioids do not induce hypothetical allodynia or other pain hypersensitivities to any significant extent
6. Opioid overdoses are universally the outcome of addictive misuse or unauthorized polypharmacy frequently including alcohol, and are statistically insignificant among pain patients, when the medication is used as prescribed
CONCLUSIONS
While it is judicious to exercise caution and continuing evaluation of the effects of the long term treatment of pain with opioids, the speculation that one MAY (the word is used at least 26 times in the Ballantyne and Mao article) encounter adverse long-term effects is not a defensible basis for assuming that they do.
What Ballantyne and Mao fail to respect is that their speculations are not supported by any substantial or factual evidence. Indeed, the contrary is true. All actual evidence and every clinical report concludes the opposite. To date, none of the allegations they presented has gained any substantial or reproducible evidence to support them. The sole exception, known for decades, is that continued therapy with opioids may induce suppression of serum testosterone levels in males, which is easily rectified with exogenous testosterone supplementation. Sadly, the Ballantyne and Mao speculations have achieved the status of “Urban Myth”, with many physicians uncritically quoting the hypothesis of hyperalgesia as an accepted fact. In fact, “Hyperalgesia” is a hypothetical theory proposed by a minority group of physicians who seek to explain why their inadequate dosing of pain results in treatment failure. There is not a single citation in the medical literature of a peer-reviewed article, based upon scientifically defensible evidence, supporting this hypothesized theory.
Caution is laudable in the practice of medicine. Ideology, masquerading as a scientifically objective review of the literature, is not.
Joel Simon Hochman MD
Executive Director
The National Foundation for the Treatment of Pain
www.paincare.org
3150 words
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