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.