5.4.2. Noribogaine for OUD
Following an earlier Phase 1 study in healthy volunteers,112 a double-blind placebo-controlled study was conducted in 27 patients receiving methadone treatment who were administered ascending doses (60, 120, and 240 mg) of noribogaine. The study investigated its effect on opioid withdrawal, safety, and pharmacokinetics.112 There no statistically significant differences in opioid withdrawal symptoms (assessed using the Subjective Opioid Withdrawal Scale [SOWS], Objective Opioid Withdrawal Scale [OOWS], and Clinical Opioid Withdrawal Scale [COWS]). Additionally, there was no difference in time to restart opioid treatment. Conversely, noribogaine produced statistically significant dose- and concentration-dependent increases of QTc interval on the ECG, although no cardiac events were noted. To our knowledge, there are no currently registered trials for OUD involving noribogaine administration.
DISCUSSION
In this review, we have summarized mechanistic and clinical findings regarding the potential of serotonergic psychedelics to treat both chronic pain and OUD. As the opioid epidemic persists, it is imperative that future research be directed toward this intersection, employing rigorous methodologies to uncover the nuanced possible effects of psychedelics on chronic pain and OUD. This concerted effort is pivotal in advancing evidence-based treatments and ultimately alleviating the burden of chronic pain, while minimizing reliance on traditional opioid-based approaches, especially among persons with OUD. Overall, convergent evidence studies provide early clinical and translational support for the use of serotonergic psychedelics for chronic pain and OUD, offering insights into their neurobiological effects, and suggesting avenues for future mechanistic research and clinical trials.
The available literature regarding the role of psychedelics for pain management is nascent but promising. Despite the nuanced needs of each type of chronic pain, such as migraines or chronic low back pain, there seems to be some common ground upon which psychedelics can exert their analgesic effects. In short, psychedelics may have the potential to alleviate pain not only through direct biological and pharmacological mechanisms (e.g., anti-inflammatory properties and reduction of central sensitization), but also through cognitive and psychological pathways (e.g., through reducing attentional bias for pain and opioid cues; counteracting fear avoidance; improving mood; and alleviating pain catastrophizing).113
However, there are also key differences between these clinical populations that warrant considerations. Many chronic pain conditions for which psychedelic treatment have been promising for, such as migraines,114 typically do not involve high opioid use rates. For other conditions, such as cancer-related pain and palliative pain, high doses of opioids are the norm.115Ultimately, different pain conditions have nuanced, variable factors that may impact their response to psychedelics and each one of them will require tailored protocols and monitoring procedures. While preliminary findings are promising for certain pain syndromes, more research is still needed to establish safety, effective dosing, and ideal administration settings across diverse chronic pain populations with varying clinical and psychosocial backgrounds.
As future clinical directions, we hypothesize that psychedelics may play a role in alleviating the burden of primarily through distinct mechanisms, as a function of the type of chronic pain and severity of opioid use at baseline. First, by alleviating episodes of acute pain, the need for high-potency analgesics such as opioids may be spared, thereby reducing the risks associated with opioids, including the potential for the development of OUD. Second, by alleviating multiple aspects of the pain experience and subjectively increasing well-being, psychedelics may have the potential to be used as co-adjuvants of a long-standing treatment for different forms of chronic pain, increasing analgesic effectiveness and potentially serving as an opioid-sparing strategy that reduces opioid-related adverse effects.
There is limited reporting across the psychedelic trials for OUD about concurrent MOUD or other treatments participants were receiving. Furthermore, the potential effects of psychedelics on different phases of OUD — ranging from current/active opioid use to acute withdrawal and later stages or recovery/maintenance — remain a critical area of inquiry, necessitating longitudinal studies to examine the full spectrum of therapeutic implications. Gaps exists about the possible effects of psychedelics in the role of psychosocial changes and changes in other recovery or harm reduction behaviors during the acute/longer term recovery phase in OUD. In addition, there is little data concerning the co-occurrence of chronic pain or changes in pain perception, despite the high rates of chronic pain in OUD.116 The dearth of comprehensive research underscores a significant gap in the literature, leaving researchers with an incomplete understanding of the potential risks and benefits at this juncture.
Despite burgeoning interest in the therapeutic potential of psychedelics for both chronic pain and SUDs, studies that specifically address these conditions in tandem are scarce. In Figure 2 , we propose various mechanisms of actions of psychedelics across the commonly discussed neurocircuitry of both addiction and its overlap with chronic pain. The biological, social, and psychological potential of these substances to influence these various neurobiological substrates with corresponding outcomes that can be assessed are described. The promising analgesic effects of classic psychedelics, the growing evidence for their utility in multiple SUDs and specifically in OUD, as well as their impact on clinical phenomena that are relevant for both chronic pain and addiction behaviors, suggest their potential as adjuncts or alternatives to traditional opioid agonist for both chronic pain and OUD.
Trial design considerations in psychedelic trials for those with pain and/or OUD
Here we lay out suggestions for future investigations and continued optimization for safety and trial design for patients with chronic pain, OUD, and/or those receiving LTOT. The goals of some of these suggestions are to optimize pain and OUD measures for trials that assess outcomes for either or both of these conditions. Specific recommendations regarding psychedelic clinical investigations were addressed in recent draft Food and Drug Administration (FDA) guidance documents and recent guidelines.117 Kiluk and colleagues also reviewed clinical trial design challenges and opportunities for emerging treatments in OUD.118,119 Addressing the existing methodological limitations is imperative for improved study design and a better understanding of the various possible uses for psychedelic medications for chronic pain and OUD, conditions with limited treatment options.