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Brain Sense and Sensitivity: More or Less?

December 6, 2020

Dr. Osunkwo presents her talk “Optimizing the
Management of Chronic Pain in Sickle Cell Disease.”

In Charles Dickens’ classic 1838 novel, Oliver Twist, a starving orphan boy living in the parish workhouse, unsatisfied by the meager portions provided by the master, says to him, “Please sir, I want some more.” He then bears the wrath of the unleashed anticipated consequences, which cascade into a domino of unanticipated “twists” of fate in his life. So it is with long-term opioid use. Chronic opioid therapy (COT) is used for the management of chronic pain in the human brain; the sickle cell brain may be no different. The µ-opioid receptor, characteristically becoming increasingly “hungry” when fed repeatedly, often requires higher and higher doses to be “filled” (tolerance). This unintended and almost inevitably predictable dose escalation leads to a plethora of undesirable consequences with repeated exposure. Adding to tolerance, is the issue of opioid-induced hyperalgesia (sensitivity) from central and peripheral sensitization. The approaches to these two consequences are divergent: “more or less?” What might make sense to both prescriber and patient may in itself cause more sensitivity.

Dr. Ifeyinwa (Ify) Osunkwo chairs the stimulating and provocative Education Program session “The Brain and Pain in Sickle Cell Disease: Understanding the Role of Sensory, Cognition and Neuropathic Pathways in the SCD Chronic Pain Experience” (live Q&A Sunday, December 6, at 2:00 p.m.  Pacific time). On the interesting and still relevant topic of long-term opioid use in our patient population (and the U.S. at large), the panel discusses the complexities from a multifaceted approach. The burden of pain in the U.S. adult population is greater than 50 percent, and despite the practice of chronic opioid use in its management,1 the evidence across all disease subgroups remains sparse. Opioids are generally initiated during an acute pain event, repeatedly prescribed for recurrent painful episodes and then escalated to daily COT. In some instances, doses higher than the threshold of concern (>120 OME in sickle cell disease [SCD]) are attained, usually unintended by both the patient and prescriber. Dr. Osunkwo suggests that the burden of management of chronic pain and opioid therapy in patients with SCD may be one of the deterrents to the recruitment of physicians to the field. The factors she proposes may be twofold: lack of comfort in the magnitude of pain management that is sometimes required, and the burden of resources needed for multidisciplinary pharmacologic and nonpharmacologic approaches to care.

Dr. Amanda Brandow kicks off the session, delineating the epidemiology and current pathophysiologic understanding of chronic neuropathic pain in SCD, from both central and peripheral sensitization. Important to highlight is that the literature supporting neuropathic pain in SCD is evolving, and so are the treatments. Dr. Brandow cautions that there is no concrete evidence in SCD itself, hence management approaches for neuropathic pain have been extrapolated from other studied chronic pain syndromes such as fibromyalgia. An algorithm for the diagnostic approach to neuropathic pain in SCD is proposed as well as a more nuanced approach to pain management. Furthermore, she encourages an expanded framework for the assessment and treatment of SCD pain that appreciates the hidden complexities of this common complication of SCD.

Dr. Osunkwo discusses the complications of chronic opioid therapy, delving deeper into opioid-induced hyperalgesia. The other consequences of COT on the brain, no less detrimental, were those on cognition, behavior, and mood, which Dr. Osunkwo elegantly compares, showing the parallels to the observations in chronic pain from other underlying disease states. The human brain responds to chronic pain and long-term opioids, potentially in similar brain mode networks, irrespective of the initiating trigger.

Building on the prior two presenters and reviewing the foundation laid by the recent pain guidelines (from the National Heart, Lung, and Blood Institute; the Centers for Disease Control and Prevention; and most recently, ASH), Dr. Long closed the session by providing a template for building a “contemporary pain management strategy for the management of acute pain in patients with SCD that includes low-dose ketamine. He highlighted the problem of the difficult-to-manage acute or chronic pain in patients, both those on long-term opioids and those with a neuropathic component to their pain. This component of management is equally frustrating for both patients and providers. Ketamine is an NMDA (N-methyl-D-aspartate) receptor antagonist. Ketamine, he suggests, is a very good option in this scenario, and he builds on the premise that multimodal analgesia is a more effective analgesic augmentation strategy, which allows for the minimization of opioid exposure without compromising analgesic benefits. Low-dose ketamine administered as a continuous intravenous infusion, is safe, with minimal potential for hemodynamic adverse effects. At doses of 1 to 5 μg/kg/hour, it allows for lower use oral and intravenous opioids. A proposed regimen is as follows: parenteral morphine sulfate, 4 mg maximum (0.1 mg/kg/hr) or hydromorphone 0.8 mg maximum (0.015 mg/kg/hr); ketorolac 30 mg every 6 hours (0.15 mg/kg); oral oxycodone 10 mg maximum (0.15 mg/kg every 3 hours); and acetaminophen 1,000 mg every 6 hours (15 mg/kg) alternating with NSAID plus ketamine 1-5 μg/kg/min. Now those are low dose opioids for anyone who has been on long-term opioids.

The session accomplishes the following goals: First, to heighten awareness to the similarities of chronic pain in SCD and in other diseases such as fibromyalgia. Chronic pain and the imprinted brain networks may be its own disease entity irrespective of the trigger. With this perspective then, we should be encouraged to draw from the experience and data from other subspecialties, as well as engage pain management specialists in the interest of a more symbiotic, bidirectional relationship. “We teach them SCD and they teach us pain management,” explained Dr. Osunkwo. Second, we must prioritize the discussion of the plethora and extent of undesirable effects opioids unleashed over time, including effects on sleep, gastrointestinal tract, cognition, mood, hyperalgesia, overall function, and quality of life. Another take-home of this session is the humble reminder that clinicians should take a step back and re-evaluate blind spots, as not all pain in patients with SCD is SCD-related. Sometimes you have to look for the “zebras,” such as autoimmune conditions, which unfortunately may co-exist.

  1. Dampier C, Palermo TM, Darbari DS, et al. AAPT diagnostic criteria for chronic sickle cell disease pain. J Pain. 2017;18:490-498.

Dr. Saah indicated no relevant conflicts of interest.

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