The administration of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to opioid-induced hyperalgesia, causing an increased sensitivity to painful stimuli. The description of opioid-induced changes in the somatosensory system has seldom been described in the setting of opioid agonist therapy in the treatment of opioid use disorders, and the few existing reports provide no guidance with respect to the effect of varied doses or substances.
The aim of the present study was to assess alterations of pain pathways among patients receiving opioid agonist therapy and to elucidate the dose-response relationship.
This study was planned as cross-sectional in an outpatient clinic in Graz, Austria. Patients receiving opioid agonist therapy for opioid use disorders (including methadone, levomethadone, buprenorphine, and extended-release morphine) were asked to fill out a questionnaire, including the central sensitization inventory. A battery of somatosensory system assessments was then performed.
A total of 120 patients participated (85 men/35 women). The mean oral morphine milligram equivalent (MME) was 694 ± 249 mg/day. Our study found significant alterations in pain perception, conditioned pain modulation, and wind-up. We demonstrated a moderate dose-response relationship between high-dose opioids and markers of central sensitization.
The present trial demonstrates the clear effects of opioid agonist therapy on the somatosensory system. Both central sensitization and descending pain modulation are negatively affected by high doses of opioids and our data elucidate a moderate dose-response relationship for these phenomena.
Opioid use disorder (OUD) affects approximately 40 million people worldwide, with substantial biopsychosocial consequences for individual health as well as socioeconomic effects for the community. Opioid agonist therapy (OAT) is a treatment strategy, targeting the same nervous system receptors as opioids, in a controlled manner, in order to reduce morbidity and mortality associated with OUD. Therefore, pharmacotherapies for OUD are administered as fixed regimens. The two most common agents used to treat OUD are the partial opioid receptor agonist buprenorphine (sometimes in combination with naloxone) and the full opioid receptor agonist methadone; however, extended-release morphine is also used in some settings. In Austria, for example, more than 50% of the patients in the OAT program are treated with extended-release morphine.
It has been previously demonstrated that the initial analgesic effects of opioids can be followed by enduring neuroplastic changes in the peripheral and central nervous systems. This remodeling can lead to paradoxical increased sensitivity to painful stimuli, which is described as opioid-induced hyperalgesia (OIH). It is caused by central sensitization of nociceptive signal transduction pathways in the dorsal horn and dorsal root ganglion.
In brief, nociceptive inputs are transmitted from receptors via peripheral nerves and subsequently the spinal cord. A reduction in the excitation threshold of the peripheral nociceptors, e.g. as a result of inflammatory processes, may lead to an increased activation, which is referred to as peripheral sensitization. The signal can also be amplified at spinal cord level or at supraspinal level, i.e. in the thalamus. This process is called central sensitization. Sensitization, on the one hand, is generally understood to be a physiological, adaptive, self-limiting process that aids in the healing of injuries. Persistent sensitization, on the other hand, is maladaptive and greatly accelerates the development of chronic pain. In contrast, a descending pain-inhibiting system can reduce or suppress incoming signals; however, in cases of a reduced function of this system, pain may be perceived even in cases of minimal nociceptive inputs. This is observed for various chronic pain conditions, e.g. fibromyalgia.
The description of opioid-induced changes in the pain pathways has largely been confined to experimental trials or analgesia in the perioperative phase. These phenomena have seldom been described in the setting of OAT, and the few existing reports provide no guidance with respect to the effect of varied doses or substances. Furthermore, changes in other neurophysiological mechanisms such as temporal summation (TS) and conditioned pain modulation (CPM), which have recently gained broad interest in pain research, have not yet been studied in the setting of maintenance OAT.
As measures of dynamic evoked pain, TS and CPM represent a means of quantifying pain modulation capability, i.e. the potency of amplification or inhibition of nociceptive inputs. CPM describes a ‘pain inhibits pain’ paradigm by assessing a pain threshold (e.g. mechanical pain threshold [MPT]) before and after the application of a painful stimuli (hot water immersion). It is regarded as a parameter for the descending inhibitory system. TS describes the ‘wind-up’ effect of repetitive noxious stimuli, e.g. 10-time application of a certain pinprick. Enhanced wind-up has been hypothesized to represent a marker for higher central responsiveness conducted by C fibers.
The aim of the present study was to assess alterations of pain pathways among patients receiving OAT and to elucidate the dose-response relationship for common medications used in the treatment of OUD.
The study was designed as a cross-sectional trial. After approval from the Ethics Committee of the Medical University of Graz, participants were recruited from the ‘Interdisciplinary Contact Point for Medical and Psychosocial Addiction Care’ outpatient clinic in Graz, Austria. Patients receiving OAT in this clinic between 1 July 2021 and 30 August 2021 were approached with an opportunity to participate in the study, and those who voluntarily provided written consent were enrolled. There were no exclusion criteria.
Participants were administered a questionnaire comprising demographic information, questions about substance use, and the central sensitization inventory (CSI) in a resealable envelope with an identification number in order to preserve their anonymity. Study staff were not present while these questionnaires were completed by the patients themselves. The CSI is a self-reported outcome measure consisting of 35 brief questions (separated in two parts). Part A of the CSI consists of 25 questions concerning common symptoms of sensitization, yielding a numeric score (0–100) reflecting the likelihood of central sensitization (with a higher score corresponding to a greater degree of symptomatology). Part B of the CSI assesses whether the patient has been diagnosed with disorders that bear relationship to central sensitization, such as anxiety or depression. As Part B is only descriptive, it was not further included in our analyses.
Each participant’s oral morphine milligram equivalent (MME) was calculated from their documented prescribed OAT regimen based on published data. In this study, 180 patients with OAT were switched from methadone, levomethadone, or buprenorphine to slow-release oral morphine. The investigators reported conversion ratios of 1:58 between buprenorphine and extended-release oral morphine, 1:11.8 between methadone and extended-release oral morphine, and 1:17.4 between levomethadone and extended-release oral morphine.
A battery of somatosensory system assessments was performed for each patient, with each test taking place in a consistent order in a secluded, quiet room at an ambient temperature of 20–21 °C, carried out by a single trained female assessor. The test battery included CPM, heat pain intensity (HPI), mechanical detection threshold (MDT), MPT, mechanical pain intensity (MPI), and TS. These parameters were selected as they are associated with different functions of the pain pathway: heat pain perception is altered in peripheral sensitization, mechanical pain parameters and TS are
