Buprenorphine blood concentrations: A biomarker for analgesia

Opioids, the frontline drugs for postsurgical analgesia, have been linked to diversion and abuse with lethal consequences. The search for safe analgesics with less harm potential has been decades long. However, clinical trials for safe opioid and nonopioid analgesics have relied on subjective pain reports, which are biased by placebo effects that increase the complexity of trials to develop new therapies to manage pain.Research in opioid naïve animals and humans demonstrates that blood concentrations of opioids that effectively saturate the morphine opioid receptor are tightly linked with patient reports and quantitative sensory tests for analgesia. Opioid drug concentrations can predict clinical responses.This report reviews preclinical and clinical evidence correlating buprenorphine pharmacokinetics with analgesia. More than 30 years of data confirm buprenorphine blood concentrations can be an objective biomarker of analgesia for moderate to severe acute postoperative pain.

Intraepidermal Nerve Fiber Density as Measured by Skin Punch Biopsy as a Marker for Small Fiber Neuropathy: Application in Patients with Fibromyalgia

Small fiber neuropathy (SFN) is a type of peripheral neuropathy that occurs from damage to the small A-delta and C nerve fibers that results in the clinical condition known as SFN. This pathology may be the result of metabolic, toxic, immune-mediated, and/or genetic factors. Small fiber symptoms can be variable and inconsistent and therefore require an objective biomarker confirmation. Small fiber dysfunction is not typically captured by diagnostic tests for large-fiber neuropathy (nerve conduction and electromyographic study). Therefore, skin biopsies stained with PGP 9.5 are the universally recommended objective test for SFN, with quantitative sensory tests, autonomic function testing, and corneal confocal imaging as secondary or adjunctive choices. Fibromyalgia (FM) is a heterogenous syndrome that has many symptoms that overlap with those found in SFN. A growing body of research has shown approximately 40–60% of patients carrying a diagnosis of FM have evidence of SFN on skin punch biopsy. There is currently no clearly defined phenotype in FM at this time to suggest whom may or may not have SFN, though research suggests it may correlate with severe cases. The skin punch biopsy provides an objective tool for use in quantifying small fiber pathology in FM. Skin punch biopsy may also be repeated for surveillance of the disease as well as measuring response to treatments. Evaluation of SFN in FM allows for better classification of FM and guidance for patient care as well as validation for their symptoms, leading to better use of resources and outcomes.

A Simplified Diagnostic Classification Scheme of Chemotherapy-Induced Peripheral Neuropathy

Background and Objective. The main purpose of this study was to develop a simple automatic diagnostic classification scheme for chemotherapy-induced peripheral neuropathy. Methods. This was a prospective cohort study that enrolled patients with colorectal or gynecologic cancer post chemotherapy for more than 1 year. The patients underwent laboratory examinations (nerve conduction studies and quantitative sensory tests), and a questionnaire about the quality of life. An unsupervised classification algorithm was used to classify the patients into groups using a small number of variables derived from the laboratory tests. A panel of five neurologists also diagnosed the types of neuropathies according to the laboratory tests. The results by the unsupervised classification algorithm and the neurologists were compared. Results. The neurologists’ diagnoses showed much higher rates of entrapment syndromes (66.1%) and radiculopathies (55.1%) than polyneuropathy (motor/sensory: 33.1%/29.7%). A multivariate analysis showed that the questionnaire was not significantly correlated with the results of quantitative sensory tests (r=0.27) or the neurologists’ diagnoses (r=0.2). All of the patients were classified into four groups by the unsupervised classification algorithm. The classification corresponded to the severity of neuropathy and correlated well with the neurologists’ diagnoses and the scales of neurological examinations. The overall correct rate of classification by the unsupervised classification algorithm was 78.8% (95% confidence interval: 73.1%-88.3%). Conclusion. The results of our unsupervised classification algorithm based on three variables of laboratory tests correlated well with the neurologists’ diagnoses.

Expression of Cutaneous Beta-2 Adrenoceptors Is Similar in Patients with Complex Regional Pain Syndrome and Pain-Free Controls

Objective Studies in rodents suggest that cutaneous beta-2 adrenoceptors (β2-ARs) mediate inflammation and pain after tissue injury and that inflammation and peripheral nerve injury trigger increases in neuronal β2-AR expression. Hence, the aim of this study was to investigate the expression of β2-ARs on keratinocytes and dermal nerves in patients with complex regional pain syndrome (CRPS). Design, Setting, and Subjects Fifty-eight patients with CRPS were recruited for this study. In addition, skin biopsies were obtained from 13 pain-free women and three pain-free men of similar age and sex distribution as the patients. Methods Quantitative sensory tests for assessing sensitivity to pressure, pinprick, light touch, heat, and cold were administered, and skin biopsies were obtained from the affected and contralateral limbs. Skin biopsies were also obtained from a similar site on the dorsal hand or foot of pain-free controls. Immunohistochemistry and confocal microscopy were used to identify β2-ARs on keratinocytes, dermal nerves, and blood vessels in the skin samples. Results The distribution of β2-ARs in keratinocytes and nerves was similar in the affected and contralateral limbs of patients and was similar for target cells in patients and controls. However, elevated β2-AR expression in reticular nerve bundles was associated with heightened sensitivity to heat pain. Conclusions These findings do not support a major role of cutaneous β2-ARs in CRPS. However, activation of neuronal β2-ARs may contribute to thermal hyperalgesia in a subgroup of patients. Whether activation of β2-ARs on keratinocytes mediates inflammation early in the course of CRPS requires further investigation.

Quantitative sensory tests fairly reflect immediate effects of oxycodone in chronic low-back pain

IntroductionQuantitative sensory tests (QST) can be used for profiling anti-nociceptive effects of analgesics. However, anti-nociceptive effects detected by QST are not necessarily associated with analgesic effects in pain patients. As part of a large investigation on low back pain, this paper describes the immediate analgesic and anti-nociceptive effects of oxycodone in chronic low-back pain and ranks different QST according to their ability to reflect this effect. The results are expected to support the selection of QST for future studies on potential novel opioid agonists in human pain.MethodsIn this randomized, placebo-controlled and double-blinded cross-over study, 50 patients with chronic low-back pain received a single oral dose of oxycodone 15 mg or active placebo, and underwent multiple QST testing. The intensity of low-back pain was recorded during 2 h. The areas under the ROC curves and 95% confidence intervals were determined, whereby responder status (≤30% pain reduction) was set as reference variable and changes in QST from baseline were set as classifiers.ResultsSignificant analgesic effect on low-back pain as well as anti-nociceptive effects for almost all QST parameters were observed. The QST with the highest area under the curve were heat pain detection threshold (0.65,95%-CI 0.46 to 0.83), single-stimulus electrical pain threshold (0.64,95%-CI 0.47 to 0.80) and pressure pain detection threshold (0.63,95%-CI 0.48 to 0.79).ConclusionsThe results suggest that anti-nociceptive effects assessed by QST fairly reflect clinical efficacy of oxycodone on low-back pain. Pressure pain detection threshold, heat pain detection threshold and single-stimulus electrical pain threshold may be more suitable to sort out potential non-responders rather than identifying potential responders to opioid medication. Future pre-clinical human research may consider these results when investigating the analgesic effect of opioid agonists by means of QST.