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17 Articles in Volume 20, Issue #1
20/20 with Lynn Webster, MD
Analgesics of the Future: Peripheral Kappa Opioid Receptor Agonists
Correspondence: Opioid-Induced Hyperalgesia; Pain Care in Older Adults
Don’t Discount the Role of Diet for Chronic Pain Relief
Editorial: Why Haven’t There Been More Breakthrough Analgesics?
Gasping for Air: Sleep-Disordered Breathing and Chronic Opioids
How can botulinum toxin be used in chronic pain syndromes?
Neurodestructive Interventions for Cancer Pain
Obesity and Pain Care: Multifaceted Considerations for Treatment
Obesity and Rheumatoid Arthritis: What Clinicians Should Know
Sickle Cell Pain Crisis: Clinical Guidelines for the Use of Oxygen
The Complexity of Sickle Cell Pain: An Overview
The Perseverance Loop: The Psychology of Pain and Factors in Pain Perception
The Rapid Rise of Non-Opioid Pain Policies
Treating Pain by Overcoming Communication Barriers
Visual Artists Tackle What Pain Looks Like
Will 2020 Be the Year of Patient Education?

Correspondence: Opioid-Induced Hyperalgesia; Pain Care in Older Adults

January/February 2020 Letters to the Editor, including a discussion on the meaning of opioid-induced hyperalgesia, and how pain care in the aging can actually be managed.
Pages 11-12

Perspective: The Real Meaning of Opioid-Induced Hyperalgesia

Dear PPM,

I don’t know how to put it delicately but the article appearing in your January 2019 issue, “Demystifying Opioid-Induced Hyperalgesia” by J. Schneider, bears an inaccurate title. It purports to “demystify” opioid-induced hyperalgesia (OIH) but in fact its thrust seems more oriented toward defending the practice of chronic opioid therapy (COT) and downplaying the significance of OIH in the non-surgical setting. There’s no respect paid to the nearly three decades of intensive basic science research on the subject, and a cursory dismissal of most of the salient clinical research (including systematic reviews and meta-analysis) via selected quotes from various expert opinion sources. The literature that is cited hails from 2005 to 2010, and we’ve learned a lot more since then.

Much of the article has little to do with OIH but rather the differential diagnosis of why people undergoing COT frequently request increased doses. The author states that OIH “has been suggested as an explanation for the decreased analgesic efficacy of opioids in some patients treated chronically with high opioid doses.” That phenomenon we call tolerance, and it may occur either pharmacokinetically (increased metabolism) or pharmacodynamically (decreased efficacy). Beyond tolerance, the author appeals to deliberate dose adjustments, increased activity-related pain ostensibly from COT facilitating more activity, and progression of underlying disease as reasons for dose escalation.

None of this, however, has anything to do with OIH, which is a distinct condition whereby exposure to exogenous opioids results in decreased pain tolerance/increased pain sensitivity – hyperalgesia. Or in layman’s terms: the drug is making the pain worse. That’s quite different from failure of the drug to alleviate pain.

The author communicates skepticism as to the validity of the condition, stating that “Dozens of experimental papers and reviews have been published, some assuming or supporting the existence of OIH and others refuting it.” A PubMed search including the terms “opioid+ induced+ hyperalgesia” in fact yields 2,300 results, and in our current culture of positive publication bias, it’s not unreasonable to speculate that the vast majority of these articles provide varying degrees of evidence base for the condition. Speculation aside, a number of systematic reviews and a meta-analyses (discussed later) show statistically significant increases in human pain hypersensitivity/decreased pain tolerance with COT.

Before considering human studies however, it’s worth pausing to discuss preclinical evidence, and there’s far more than “some evidence of OIH in rats.” Various mechanistic interpretations for the development of OIH have involved contributions from the NMDA/glutaminergic system, TRPV-1 and BDNF activities, the KOR/dynorphin system, etc., but arguably the most intriguing research over the past two decades comes from the lab of Dr. Linda Watkins’ at the University of Colorado (with a growing international collaboration). They have elegantly demonstrated using both in vitro and in vivo models a microglia-mediated CNS inflammatory state (with downstream systemic inflammation as well as central sensitization phenomenon) resulting from chronic opioid (as well as other xenobiotic) activation of Toll-like receptor 4 (TLR-4) and its myeloid differentiation 2 (MD2) co-receptor.

This phenomenon is particularly fascinating in that application of low doses of naltrexone (which readily crosses the blood-brain barrier) serves to antagonize the TLR-4/MD2 heterodimer on microglia and ameliorate OIH: note that both the CNS-inflammatory effects of COT and the anti-inflammatory effects of naltrexone occur independently of opioid receptors mu, kappa, or delta. Even more fascinating perhaps is the fact that the (+) enantiomer of naltrexone exhibits no activity at opioid receptors but still blocks the hyperalgesia-inducing effects of opioids via TLR-4.

Numerous human experimental studies, the breadth of methods and findings of which are beyond the scope of a cursory overview such as the article in question (or this response), clearly support nearly universally reproducible causal association between even short-term COT and OIH. Two recent systematic reviews and a meta-analysis1,2 both clearly validate not only the prevalence of the condition, but also conclude that it is a “significant outcome within the nonsurgical setting.”1

The issue at hand is the claim the author makes that, “The clinical relevance of opioid-
induced hyperalgesia in the setting of opioid therapy for chronic pain has never been shown.” It is unlikely that a randomized controlled prospective trial of exposure to an intervention which carries high risks (COT) looking for an adverse outcome (OIH) will ever occur. By that logic, the clinical relevance of not only OIH but also constipation in the setting of COT will likely never be shown.

That doesn’t however justify turning a blind eye to the probability, or even the possibility of OIH or any adverse drug effect really. The only rational way to approach this issue at both an individual and also population level is to recognize that resolution of (or at least improvement in) pain upon discontinuation of chronic opioid therapy, essentially the sine qua non of OIH, has been shown in numerous prospective investigations, and a recent systematic review of 20 studies ( n = 2,109) patients showed that 85% of the time COT reduction improved pain while the other 15% of the studies included showed stability and not worsening.3 Anecdotal evidence from many of our practices around the country, and unpublished data from our practice comprising greater than 200 individuals’ experience corroborates the literature.

“If you don’t think of it, you won’t diagnose it” we’re taught in medical school. An even more effective way of avoiding making the tough call is to refuse the evidence and label it myth.

– Heath McAnally, MD, MSPH, DABA, DABPM


Dear Dr. McAnally:

I appreciate your detailed perspective and especially your inclusion of several recent references, all of which were published after the publication of my article. I completely agree with the statement “resolution of (or at least improvement in) pain upon discontinuation of chronic opioid therapy is essentially the sine qua non of OIH.” My observation that no clinical studies have demonstrated the relevance of OIH, if it exists, was based exactly on this premise – that evidence of OIH in the clinical setting would require a decrease of pain when opioids are tapered or discontinued. But I reject the implication that I refused the evidence and labeled it a myth. What I did question was the relevance of the published studies to patient care.

This concern was echoed by Yang, et al, who reviewed eight studies involving pain sensitivity to noxious stimuli in humans, and commented at the end, “None of the trials explored clinical outcomes, such as effects on opioid consumption.”1 “Due to conflicting conclusions and various limitations, the clinical impact of OIH could not be assessed. Clinicians should monitor for effects of OIH in the nonoperative setting because there is insufficient evidence from the available literature to conclude that OIH is consistently observed in this setting.”

Of the three recent studies you referenced, only one, by Fishbain, et al,3 attempted to directly answer the question of whether opioid tapering in chronic pain patients result in improved or unchanged pain versus increased pain at taper completion. Fishbain reported: “There is consistent type 3 and 4 study evidence that opioid tapering in CPPs reduces pain or maintains the same level of pain. However, these studies represented lower levels of evidence and were not designed to test the hypothesis, with the evidence being marginal in quality with large amounts of missing data. These results then primarily reveal the need for controlled studies (type 2) to address this hypothesis.”3

Fishbain’s findings about opioid tapering do not prove that the reason for these results was simply the presence of OIH. Pain has multiple causes, and optimal treatment of chronic pain involves a multimodal approach.4 All too often, however, after initial assessment and acute treatment, ongoing management of chronic pain consists only of an opioid prescription, with less attention to an ongoing exercise regimen, behavioral health assessment and treatment, other medications, alternative modalities, etc. Effective opioid tapering needs to implement these other modalities.5 Success in tapering thus may depend on ameliorating other factors that have contributed to the chronic pain such as psychological (anxiety, depression, PTSD), deconditioned muscles, and so forth.

Regarding this, Fishbain writes in his December 2018 review, “Most of the studies in this review involved centers where additional multidisciplinary treatments may have a positive impact on the tapering process.”3 The patients “thereby received other treatments besides opioid tapering that could have had a significant impact on the chronic pain patient’s pain. These studies did not control for the effects of this treatment. It is possible that the drop in pain was the result of those treatments rather than opioid reduction.”

Another limitation of the study, according to Fishbain, was that: “In five of the studies, or 25.0% of the studies in this review, adjuvants were utilized during tapering, and the use of these drugs was not controlled for. However, it is likely that adjuvants were utilized in the majority of the studies, but this information was not provided. This is likely as the majority of the patients were tapered in multidisciplinary facilities, where such treatments would normally be utilized.”3

Thus, the finding that opioid tapering does not necessarily increase pain and can decrease it is not proof that OIH was the cause of the pain.

The definition of “hyperalgesia” is an exaggerated pain response, classically found in neuropathic pain syndromes. Otherwise, the most common context in which hyperalgesia is alluded to is in patients on high-dose opioids, when a common explanation (especially by medical insurance companies) is that it’s because the opioids themselves caused it (ie, OIH). The reason I carefully explained why patients often request some dose increase at some point is not that I did not understand the difference between tolerance and OIH, but rather that by extension, clinicians often conflate the two, believing that the reason patients require dose increases is that the opioids themselves have produced the increased pain rather than because of the reasons I described in my article.

Overall, my article was focused on the clinical relevance of OIH. It may well exist, but of concern to clinicians is its role in decision-making regarding the use of opioids. OIH is frequently cited by insurance companies as a reason not to pay for opioids for chronic pain, but its clinical relevance has still not been proven.

– Jennifer Schneider, MD, PhD


Pain Care in the Aging: What Can Seniors Actually Afford?


Dear PPM,

Regarding “Balancing Pain Care – and Opioids – in the Aging Adult” (Reid C, Nov/Dec 2019 issue), there are some very good points, but also a failure to acknowledge the reality of how limited the options are for seniors. Mental health coverage for Medicare insured seniors is abysmal and, thus, the likelihood they can find funded CBT or other mental health interventions is slim. If they do find a LCSW or PhD (the only categories of mental health providers Medicare acknowledges), it is unlikely the provider has any experience in counseling those with chronic pain or with opioid dependence.

And good luck finding a multidisciplinary pain management program outside of some university grant-funded program. CMS would much rather spend $8,000 on a series of semi-pointless steroid injections or $35,000 on spine surgery than to cover massage therapy, supplements, yoga, etc. Opioids, injections, and surgery are what’s covered, so guess what seniors are going to get?

– Michael Whiting, MD

Last updated on: February 3, 2020
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Correspondence: Continuing the “Pain Specialist” Dialogue
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