Misuse of ‘Hyperalgesia’ to Limit Care
John (not his real name) is a 51-year-old chronic pain patient that I have been seeing since 2003. His pains began in 1981 with a motor vehicle accident. In1985 he broke an ankle and in 2000 he developed chronic inflammatory demyelinating poly-neuropathy. John had another motor vehicle accident in 2002, developed diabetes and, in 2008, added a diagnosis of Stage IV lung cancer. This year, he fell and injured his hip. Each event added, in its own way, to his chronic pain complaints. Multiple therapists had tried multiple approaches to his pain treatments, starting with Lorcet in 1981 and including IVIG therapy in 2002, and chemo and radiation therapy in 2009 and 2010.
In 2003, I had begun carefully titrating him on oxycodone, Oxycontin® and Dilaudid®, which had been started by another doctor and, ultimately, settled on a dose of Oxycontin 640mg B.I.D., 32mg hydromorphone q 4 hrs prn breakthrough pain and Xanax® 1 to 1.5mg q.i.d. prn muscle spasms and anxiety. On these medicines, he was content and functional and denied any deficits or side-effects due to his medicine. His insurance company was concerned about the expenses of his medicine and asked me to arrange for a second opinion. Given the complicating factor of his end-stage lung cancer, I arranged for an evaluation by the pain clinic of a major cancer center. He was examined and evaluated by a junior and more senior doctor but had no neurologic tests performed. Specifically, he was not tested for allodynia, hyperpathia, reflex changes, temperature sensitivity, muscle spasms, joint tenderness, autonomic neuropathy, etc. The report stated that his opiate daily intake was “very variable” and that “he would likely benefit from establishing a scheduled long-acting or extended-release dos-age and rely on the use of a short acting pain medication for breakthrough pain and/or variability in his pain.” This was, in fact, exactly what we had been doing for years. Further, the report stated “given his high doses, the patient is likely suffering from opiate-induced hyperalgesia and would actually benefit from weaning his daily opiate intake.”
“...the insurance company was refusing to pay for [the patient’s] medicines until I gave them a report on my plan to take him off his medicines. When I reviewed the second opinion report with [the patient], he was incensed and told me his medicines had worked well for years and he had no desire for me to change anything.”
My patient contacted me on a Friday afternoon and told me the insurance company was refusing to pay for his medicines until I gave them a report on my plan to take him off his medicines. When I reviewed the second opinion report with him, he was incensed and told me his medicines had worked well for years and he had no desire for me to change anything. I was not entirely averse to trying a different approach but was reminded of a recent review of pediatric opiate-induced hyperalgesia. It primarily suggested that OIH was best avoided by not using opioids in children, yet all the other approaches were experimental.1
Opioid-induced hyperalgesia seems to be a well-established rat phenomenon but remains controversial in humans. Fishbain et al did an evidence-based structured review of 504 articles on OIH in humans and animals.2 They addressed ten hypo-theses that had been utilized to test for the possibility of OIH in humans. Only studies performed on opioid naïve, pain-free volunteers that were given opioid infusions met criteria for quality evidence—and even those studies showed inconsistent results.
A study by D. Andrew Tompkins, MD and colleagues at Johns Hopkins School of Medicine compared the effects of repeated alfentanil and diphenhydramine injections on normal opioid naïve, pain-free volunteers.3 Evidence of “OIH” developed in the antihistamine group, but not in the opioid group. Another study by Robert Edwards, PhD and colleagues at Harvard Medical School and Brigham and Women’s Hospital prospectively studied 204 patient with chronic spinal pain and recorded their responses to pain tests—including pressure from a punctuate probe, increased pressure from a mechanical device and heat and cold sensitivity to contact thermode. They found individuals with lower thresholds and decreased tolerance to pain in approximately 65% of both opioid and non-opioid exposed patients. There was no significant difference in tolerance and pain thresholds to punctuate or pressure stimuli be-tween the two groups.
After a review of the literature and my clinical experience, I agree with Gavril Pasternak, MD, PhD, the distinguished opiate researcher at Memorial Sloan Sloan-Kettering Cancer Center who has stated, in reference to hyperalgesia, “There is little question that it exists. The animal models can reliably detect it and, if you look closely enough, you might be able to detect it in human subjects. However, in the clinical setting it rarely, if ever, has a sufficiently robust effect to become a significant issue in the absence of metabolic abnormalities including hypercalcemia or renal insufficiency.”
Although stable ambulation can occur with a section of the fibula removed, it was found that resection of the fibula segment close to the tibiofibular joint resulted in significant ankle instability. Consequently, by resecting parts of the distal fibula, a mobile remnant is produced which causes an inability to withstand loading pressure. This instability is partially due to the compromised integrity of the interosseous membrane between the tibia and fibula.5 In a study done by Thordarson et al, it was found that displacement of the fibula by a shortening or lateral shift of two millimeters, together with five degrees or more of external rotation, increases the contact pressures in the ankle joint and causes ankle instability.6
I have been practicing Pain Medicine for thirty years and remember the struggles we went through to establish the reasonableness of chronic opioid therapy in the ethical treatment of chronic non-malignant pain patients. I am afraid that our concern with the laboratory curiosity of OIH will end up feeding opiophobia and will be used as an excuse by clinicians to avoid the complexities of opioid analgesia or by insurance companies to limit access to care for “expensive” chronic pain patients. In our attempts to optimize therapy for chronic pain patients, we must be careful not to “throw out the baby with the bathwater.”