Frozen in Addiction: A New Wave of Drug‐Induced Movement Disorders?

Movement disorders resulting from illicit drug use can present with both hypokinetic and hyperkinetic features often leading to severe functional impairment. The seminal publication by Langston and colleagues,1 for example, described four adults who became parkinsonian within a week of being exposed to heroin contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These first cases marked the beginning of sporadic outbreaks of parkinsonism linked to synthetic opioid use.2 The cause was attributed to MPP+, a MAO-B metabolite of MPTP, which results in mitochondrial dysfunction and neuronal death.2 Importantly, although these cases affected relatively few individuals worldwide, they were pivotal in highlighting the vulnerability of dopamine-producing neurons to a variety of neurotoxins and established groundbreaking models for studying Parkinson's disease (PD).2 Other examples of drug-induced movement disorders include dystonia-parkinsonism resulting from manganese toxicity due to ephedrine (methcathinone) use3 and chorea and dystonia—also referred to as “crack-dancing”—or tics caused by cocaine use.4 Over the past few years, a new and much larger-scale trend of people with movement disorders caused by illicit drug use has emerged. This phenomenon appears to be driven by synthetic opioids such as fentanyl and its analogues, often combined with the veterinary sedative xylazine, the combination colloquially known as “tranq,” as well as methamphetamines.5-7 Although the epicenter is the United States and Canada, cases have been reported by prominent media outlets in various parts of the world.7-11 Affected individuals commonly exhibit characteristic postural and other motor abnormalities, which from a phenomenological standpoint have important similarities with movement disorders such as camptocormia in parkinsonism or generalized dystonia. This hypothesis-driven connection has not been sufficiently considered, despite its potential to deepen our knowledge about the mechanisms modulating postural motor control. Given the alarming prevalence of this phenomenon, it further holds significant implications for public health. Here, we draw from our own experience and use knowledge from neuroscience of motor control and movement disorders to speculate about the relationship between abnormal postural control and regular exposure to illicit fentanyl, xylazine, and methamphetamines, including combination use. We also highlight open questions that will need to be addressed in future research. A characteristic phenotype linked to the current drug-use epidemic reported in the media is people with markedly bent spines, often flexed forward and while standing.7-11 This distinctive posture that is primarily attributed to fentanyl drug use, and its various mixtures, including methamphetamines and xylazine,5, 6 has drawn worldwide attention (see Supporting Information Data S1). However, postural abnormalities linked to opioid use have been noted for some time, including forward head posture and thoracic “hyperkyphosis.”12 Slang terms such as “heroin hunch” or “fentanyl fold” are often used to describe the effects of high-potency synthetic opioids on the body, which are arguably most often acute and initially reversible. Notwithstanding, it is documented that some people may have persistent postural abnormalities (Fig. 1, Video S1), even in cases after cessation of drug use.13 At this point it is unclear why some individuals are at higher risk for permanent postural changes. In fact, this issue is so prevalent and disabling that physical rehabilitation to specifically address it is often part of comprehensive opioid recovery programs.14 From a phenomenology standpoint, the bent spines of people with daily illicit synthetic opioid use can look strikingly similar to camptocormia, as seen in parkinsonism. The latter describes the involuntary marked flexion of the thoracolumbar spine that appears during standing or walking and may resolve in the supine position.15 Camptocormia is not uncommonly a feature of PD, with prevalence estimates up to 17% depending on the diagnostic criteria that are applied and the disease duration, among other factors.15 The pathophysiology of parkinsonian camptocormia is poorly understood, even though it appears to be driven by several contributing factors that might play their role at different times during the progression of the condition. These include myopathic changes, alterations in postural control and proprioceptive reflexes, hyperactivity of axial flexors, and possibly musculoskeletal inflammation.16 Importantly, there appears to be a crucial relationship between dopaminergic transmission and camptocormia supported by several layers of evidence, including cases of camptocormia caused by dopamine blocking agents,17 as well as by dopaminergic drugs such as dopamine agonists used for PD,18 after exposure to MPTP1 or as a result of damage in the basal ganglia, as in the case of putaminal stroke.19 Strikingly, prominent postural abnormalities and camptocormia were also reported in cases of postencephalitic parkinsonism.20 Moreover, severe postural changes resembling those observed in people during acute intoxication with synthetic opioids have been reported in monkeys after bilateral lesions of globus pallidus and were described as “somersault,” “flexed,” or “pallidal” postures.21 This suggests that the bent spine phenomena seen in the current wave of illicit drug use could be linked to striatal dopamine neurotransmission or other basal ganglia disturbances. Despite the apparent overlap between the postural changes currently observed in people with illicit synthetic opioid use and camptocormia, it is remarkable that there is little published about this potential relationship. The lack of research might be linked to challenges with access to health care for people with illicit synthetic opioid use. For example, among the five cases we have seen in our clinics, only one returned for a scheduled follow-up appointment. One recent systematic review looked at the different movement disorders reported in the literature in association with opioid use disorder and identified only 39 reported cases, 5 with parkinsonian features, 5 with dystonia, although it was not specified whether it was axial, and 3 with postural instability.22 As a result, much of the knowledge of this phenomenon comes from traditional and social media. A list of links of the most viewed videos on YouTube and X on this topic is provided in Supporting Information Data S1. Based on the cases we have seen and aligning with the videos showcased in the media and social networks, there is variability in the motor phenomenology, which may be either acute (ie, while being intoxicated), and reversible, or in some cases also chronic. In the latter scenario, the forward flexed posture is often accompanied by a lateral bend, reminiscent of Pisa syndrome (see Fig. 1C and Video S1). Moreover, although in some individuals the overall posture—with bent spine, flexed arms and legs—may resemble that seen in PD, there can be differences, and there is a clear dissociation between these striking postural abnormalities and other features along the akinesia spectrum. In several cases, for example, gait speed remained normal despite the abnormal posture9, 13, 23 (also see Video S1), suggesting that the postural phenotype dominates the clinical picture, with other parkinsonian, appendicular signs being mild or absent altogether. Alternatively, some cases show a different postural abnormality of axial hyperextension akin to generalized dystonia.24 In our clinics, we have observed one individual—currently enrolled in a recovery program—who, during episodes of acute intoxication, presented with variable postures, including flexion of the upper body and knees on some occasions, and truncal hyperextension on other occasions akin to acute dystonic reactions. Although these observations might suggest different pathophysiological underpinnings, the shared and prominent involvement of the axial musculature would support impairments in the mechanisms associated with postural control. Importantly, these postural abnormalities may represent a common final pathway of multiple upstream mechanisms, rather than reflecting a single shared pathophysiology. So far, the most common explanation provided for the acute presentations of opioid-related postural abnormalities focuses on the link between arousal and motor control.9 Specifically, it is hypothesized that the reduced level of consciousness caused by drug intoxication may underlie the temporary changes in axial muscle control that lead to forward truncal flexion. Sleep literature provides some support for this hypothesis. Muscle atonia is a characteristic phenomenon of rapid eye movement (REM) sleep and is one of the defining features of pathological conditions such as narcoleptic cataplexy.25, 26 However, in these instances, muscle atonia also typically involves the lower limbs and leads to falls, which does not seem to happen with illicit synthetic opioid use, as evidenced by the ability to maintain a standing position or to walk despite severe truncal flexion. Therefore, this hypothesis does not adequately explain the postural motor phenomena we highlight in this article. Another suggested mechanism involves the induction of muscle rigidity during acute fentanyl exposure, particularly axially involving the jaw and the thoracic area. This phenomenon, referred to as the “wooden chest syndrome” (WCS),27 was originally observed when fentanyl was introduced in surgical anesthesia several decades ago, but is now commonly documented with street drug use.28, 29 The WCS is characterized by the acute onset, typically within the first few minutes, of muscle rigidity and is associated with rapid increases of fentanyl concentrations in the blood. It is related to high mortality and is, in fact, quite common in documented overdose cases involving synthetic opioids.27, 28 It has been argued that WCS is the result of increased noradrenergic output from the locus coeruleus, possibly to the spinal cord30 as a result of μ-receptor activation, although other hypotheses have been put forward highlighting a role for cholinergic neurotransmission.28 Although the WCS and the postural abnormalities we are highlighting in this article are phenomenologically different, there remains the possibility that the latter is similarly induced by muscle rigidity of different muscle effectors (eg, of the abdominal wall). A third hypothesis could involve the disruption of dopaminergic neurotransmission and may provide links between changes in body posture in people with illicit synthetic opioid use and camptocormia in parkinsonian conditions. Addiction literature has long established the interplay between μ-opioid receptor activation and dopaminergic neurotransmission.31-33 Models of fentanyl exposure have documented the downregulation of cortical D1/D2 receptors,34 alongside alterations in dopamine binding, dopamine transporter availability, and striatal dopamine release.35-38 Many of these effects are mediated through fentanyl's direct actions on GABA, which in turn regulates dopaminergic neurotransmission.32, 33 Although not all studies support effects of opioids on the nigrostriatal system,39 it is noteworthy that chronic exposure to tramadol, another synthetic opioid, is known to induce parkinsonian symptoms in humans and increases the risk of developing PD.40, 41 Moreover, tramadol also interferes with [(123)I]FP-CIT SPECT scans.42 In addition, opioids can exacerbate rigidity in parkinsonism, with symptoms unresponsive to dopaminergic therapies but reversible with fentanyl discontinuation at least in one case.43 Theoretically, depending on the regional distribution and state of activation, μ-receptor stimulation in the striatum might lead to either a reduced or enhanced downstream motor output, potentially mediated by the involvement of additional neurotransmitter systems. This could result in hypokinetic or hyperkinetic motor manifestations, presenting as postural abnormalities akin to camptocormia and dystonia, respectively.22 Several additional mechanisms could independently or synergistically contribute to the postural abnormalities observed in people with illicit synthetic opioid use. Fentanyl exposure and overdose have been causally related to structural brain damage,44-46 and similar postural abnormalities have indeed been documented after basal ganglia lesions, as described earlier.19-21 This is often confounded by hypoxia, another common consequence of opioid use, which also induces widespread brain injury and may independently lead to postural abnormalities and changes in motor control.45 The cerebellum, for example, which plays a key role in axial motor control and postural tone,47, 48 can be a direct target of opioid neurotoxicity.49, 50 Moreover, the current wave of the opioid crisis encompasses different combinations of drugs, specifically stimulants, such as methamphetamine and cocaine, that are intentionally and unintentionally coadministered with fentanyl, its analogues, and xylazine.5 Indeed, in some of the cases we observed, long-term opioid use alone did not cause severe postural abnormalities. These emerged only over recent years, after exposure shifted to higher-potency and synthetic opioids and combinations with other drugs (Fig. 2). For example, although acute intoxication with stimulants, such as methamphetamine, is causally associated with hyperkinetic movement disorders such as chorea and tics,4 long-term stimulant use is known to cause dopaminergic cell loss and increases the risk for later development of parkinsonism.51-53 As far as xylazine is concerned, it predominantly functions as an α2-adrenergic receptor agonist, resulting in reduced norepinephrine release.54 Noradrenergic transmission is tightly linked to the maintenance of postural muscle tone,25 and this might, therefore, represent an additional mechanism contributing to the postural abnormalities observed in people with illicit drug use involving synthetic opioids. There is also evidence of synergistic effects between fentanyl and xylazine, and it has been suggested that the motor phenotypes linked to the current drug crisis have been exacerbated with the increasing adulteration of fentanyl with xylazine.55 Indeed, chronic exposure to fentanyl induces changes to dopaminergic function,31, 38 and xylazine appears to enhance the physiological effects of fentanyl.55 In fact, xylazine was shown to increase dopaminergic availability in the nucleus accumbens (via α2-adrenergic receptor activation), increasing the action of fentanyl.55 Unfortunately, there are no studies to prospectively document the neurotropic effects of the various drug mixtures driving the current opioid crisis. Importantly, we have never before witnessed the widespread, unregulated use of such ultrapotent synthetic opioids that are often combined (Fig. 2). As such, the full spectrum of their effects on the human brain—particularly with chronic exposure or polysubstance use—remains unknown. Finally, peripheral factors should be considered, specifically in chronic cases with permanent changes. There is a high probability that repetitive episodes of acute postural changes over several hours every day and for long periods (eg, months or years) may lead to secondary musculoskeletal changes that may become irreversible. Literature documents pressure injuries and disc pathology, including recurrent episodes of vertebral osteomyelitis as a result of peripheral tissue necrosis and septicemia, which may further complicate the clinical picture.56 To date, there is very limited research on the range and phenomenological features of the postural abnormalities attributed to the current wave of synthetic opioid use. Many key questions remain unanswered (see Table 1). Addressing them will not only clarify the possibly multiple contributing causes behind the striking motor phenomena observed in people with daily illicit synthetic opioid use but may also provide unique insights into the physiology of postural control in health in general. It may also allow us to deepen our understanding on the pathophysiology of axial changes such as camptocormia and Pisa syndrome in parkinsonian syndromes such as PD and possibly truncal dystonia. This effort will require a multidisciplinary approach, leveraging collaborations between addiction medicine physicians, psychiatrists, neurologists, allied health professionals, and motor neuroscientists. Supervised consumption and other harm-reduction service sites may provide valuable settings for studying the acute and long-term effects of synthetic opioids and related substances on motor control and postural systems. This may lead to much-needed carefully conducted studies that meet necessary ethical and legal standards to understand the causes behind these phenomena and ways to help affected individuals, including prevention of the persistent phenotype and its consequences. In addition, postmortem studies may yield valuable insights by showing structural or biochemical changes in neural systems that regulate posture and movement, even though their interpretation could be complicated by cumulative drug exposures and other vascular, inflammatory, or infectious processes. Clearly, the vulnerable populations affected by these substances face life-threatening challenges, and we are increasingly and painfully aware of their urgent short-term needs, including receiving care for infectious diseases or overdoses. However, it is critical to understand as early as possible whether these individuals are also at risk for long-term neurodegenerative disorders. There are, of course, ethical and major logistical issues that need to be carefully addressed when considering research studies with these populations. However, the emergence of this distinctive phenomenon presents a unique opportunity to investigate the effects of opioids on the motor system, specifically axial motor control. Indeed, despite their apparent involvement in different movement disorders,22 opioids have rarely been the focus of motor neuroscience research beyond the scope of motivation and addiction. The current opioid epidemic, with its devastating consequences, mandates neuroscientific exploration that may translate to novel mechanistic and therapeutic approaches for movement disorders of postural control. Failure to pursue this research risks perpetuating the neglect of the current epidemic beyond addiction medicine and leaving many aspects of its neurological impact unaddressed. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. C.G.: 1A, 2B, 3B, 3A. R.E.: 1A, 1B, 1C, 3A. M.A.: 1B, 1C, 3B. T.S.H: 1C, 3B. D.C.: 1C, 3B. C.S.: 1B, 3C. P.S.: 1B, 1C, 3B. C.M.: 1C, 3B. S.H.F.: 1C, 3B. A.F.: 1C, 3B. A.E.L.: 1C, 3B. J.S.: 1A, 1B, 3B. K.P.B.: 1A, 1B, 3B. This work was supported by the Wolf Chair for Neurodevelopmental Psychiatry, a joint Hospital-University Named Chair between the University of Toronto, UHN, and the UHN Foundation held by C.G. C.G. holds the Wolf Chair for Neurodevelopmental Psychiatry, a joint Hospital-University Named Chair between the University of Toronto, UHN, and the UHN Foundation. He received honoraria from the Movement Disorder Society for educational activities. R.E. receives royalties from publication of Case in Movement and University and Movement has received from and and has received honoraria for from the and Movement Disorder and no receiving as a for and as an for in the past is the for receives support from the and UHN with research from The of Canada, and has received honoraria from the and Movement Disorder has received and by and and has received royalties from University was a for clinical with and received research from the Parkinson's The the and Movement Disorder the and the Foundation. has as an for 2B, and has received honoraria from and has received from of The Parkinson's Canada, and The is as an in related to and Parkinson's and has received royalties from and University receives royalties from publication of the Parkinson's and Other Movement University of Movement University and Case in Movement and University has received for as from and has received honoraria for at from and and from the of and the and Movement Disorder and is also supported by a research from the Data not to this article as no were or during the current Data S1. Supporting The is not for the or of by the than should be to the for the article.