■ Introduction

Substance use disorders (SUDs) continue to pose a major public health concern due to their high incidence, chronic nature and wide-ranging
consequences for individuals and societies worldwide [1, 2]. While these conditions are often seen mainly as compulsive drug use and difficulty
with self-control, more evidence reveals that SUDs rarely occur in isolation. Instead, they are frequently associated with complex alterations in emotional states and pain perception [3, 4]. A growing body of literature suggests that disturbances in emotio­nal regulation and pain sensitivity can both initiate and perpetuate substance misuse, thereby intensifying the severity and chronicity of SUDs [4-6]. Converging evidence points to overlapping neuro­biological pathways underlying pain perception and addictive behaviours, including alterations in frontocortical circuitry [5, 7, 8], periaqueductal gray (PAG) [9] and the central amygdala-corticotropin- releasing factor-1 (CeA-CRF1) system [10].

From adaptive pain signalling to pathological hyperalgesia

Pain, a sensory and affective experience related to actual or potential tissue damage, serves crucial protective functions under normal conditions [6]. Heightened pain responsiveness like hyperalgesia (increased sensitivity to painful stimuli) and
allodynia (perception of normally harmless sti­muli as painful) can be adaptive when tissues are healing. However, when these responses outlast the initial cause, they may transform into persistent pathological states sustained by central mechanisms in the nervous system [6]. This increase in pain sensitivity often interacts with nega­tive affective states and maladaptive behaviours, including substance misuse aimed at managing dis­ comfort [11, 12].

The self-reinforcing cycle

Though acute administration of psychoactive substances may temporarily reduce pain or distress, chronic heavy consumption contributes to neurobiological adaptations that intensify pain sensitivity and increase negative emotional states. Consequently, as users attempt to soothe their suffering through these substances, they are caught in a self-reinforcing cycle: continuing substance use induces neuroadaptations that worsen pain perception, which in turn can lead to withdrawal- associated discomfort and compel further substance intake [3, 5, 10, 13, 14].

Affective dysregulation and pain vulnerability

The connection between SUDs and pain becomes even more significant when considering how emotional dysregulation affects both. Nega­tive emotional states like stress, depression and anxiety, frequently emerge in individuals with SUDs, and are critical factors in the shift from recreational to compulsive use [1, 7, 8, 10, 15]. Importantly, pain can also be a somatic manifestation of depression or anxiety even in the absence of any identifiable tissue or organ damage [16], further blurring the line between affective distress and nociceptive experience. In turn, chronic pain can further exacerbate these negative emotions and motivations, increasing the likelihood that people will turn to substances as a short-term coping strategy [12, 14, 17-19].

Established models of substance-induced hyperalgesia

Opioid [20-22] and alcohol [23-26] induced pain dysregulation have been thoroughly investigated in the literature. Hyperalgesia secondary to opioid use has been linked to the enhancement of pronociceptive systems like the Transient Receptor Potential Vanilloid 1 (TRPV1), NMDA receptors and microglia as well as the decline of antinociceptive systems like beta-arrestin 2 [22]. Alcohol-induced hyperalgesia mechanisms correlate with the activity of tyrosine kinase, protein kinase C (PKC) and NMDA (N-methyl-D-aspartate) receptors in spinal cord motor neurons as well as with glutamatergic circuit pathways, GABA (gamma-aminobutyric acid) receptors, adenosine receptors and calcium channels [27, 28].

Current gaps and review focus

This review will not further address the pre­viously mentioned extensive understanding of opioid- and alcohol-induced hyperalgesia and its broad clinical implications. Instead, the focus will be on less-studied psychoactive substances such as nicotine, stimulants, cannabis and benzodiazepines, as preliminary evidence indicates that these agents can also modulate pain processing at both peripheral and central levels. 

In addition to examining substance-specific hyperalgesic mechanisms, we will also present evi­dence for oxidative stress associated with chronic exposure to the psychoactive substances discussed in this review. Meta-analyses and systematic reviews suggest that increased oxidative stress and compromised antioxidant defences could play a role across many chronic pain conditions including migraines, endometriosis, neuropathic, inflammatory syndromes and others [29-33]. In this context, it is reasonable to hypothesise that substance-induced oxidative imbalance may represent one of the biological processes potentially contributing to pain vulnerability or persistence in individuals with long-term exposure to psychoactive drugs. Accordingly, the sections that follow will document substance-specific evidence of oxidative
stress, without discussing its potential relevance to pain in each instance. 

Since the data on changes of pain processing in human subjects remains scarce, we analysed the results of studies referring to associations between pain and all kinds of problematic substance use i.e.: substance dependence, substance harmful or risky use and substance use disorder (as defined by DSM-5).
Therefore this review refers to a broad phenomenon of “problematic substance use”, which is not nosologically defined, yet is clinically and epidemiologically utilised [34, 35]. 

By identifying existing gaps and integrating current knowledge, we intend to contribute to more effective and well-rounded treatment stra­tegies. A complete, systematically organised overview of the neuroadaptive mechanisms that drive hyperalgesia for each substance discussed below is provided in Table I.

■ Pain dysregulation across psychoactive substance classes

Nicotine

Nicotine exposure through tobacco and related products remains a major global public health concern, with roughly one in five adults worldwide addicted to tobacco, according to the newest WHO global report [36] and tobacco use being responsible for more than 7 million deaths every year [37]. The prevalence of nicotine use among individuals with chronic pain is estimated to be twice as high as in the general population [38], with patients reporting pain coping as a primary reason for tobacco smoking [19] as well as tobacco smoking increasing pre-existing pain [39].

Neurobiological mechanisms based on preclinical studies

A single draw on a cigarette activates α4β2 and α7 nicotinic acetylcholine receptors on peripheral afferents and spinal–brain-stem circuits, temporarily damping nociceptive signalling [40]. A few weeks of chronic smoking desensitise and up- regulate α4β2 receptors, diminishes this inhibitory effect and leads to hyperalgesia [41]. This effect reinforces the urge to smoke to gain immediate pain relief, thereby sustaining a positive feedback loop and maintaining tobacco dependence [42].

Studies on human populations

Findings on the contribution of chronic nicotine to heightened pain sensitivity are supported not only by multiple preclinical studies on rodent models [15, 43, 44], but also by a notable increase in the number of human studies published in recent years. A very recent Mendelian randomisation study by Zhang and Liang [45] based on FinnGen and UK Biobank datasets investigating an association between smoking and co-occurrence of pain related diseases identified smoking as a predictor of numerous pain conditions like, among others, dorsalgia, angina pectoris, sciatica and lower back pain.

Khan et al. [39] conducted a propensity-weight­ed analysis involving over 8,000 male and female patients to investigate the independent effects of smoking on individuals with chronic pain. The study compared smokers and non-smokers  across various domains using PROMIS (Patient- Reported Outcomes Measurement Information System). A linear mixed-model analysis revealed that, at the time of pain consultation, smokers reported significantly greater pain intensity, pain interference and pain behaviours as well as physical dysfunction than non-smokers. These adverse effects were persistent and were consistent within the chronic pain population. Moreover, smoking emerged as a predictor of poor recovery and mini­mal improvement in the long term. 

There is further support for nicotine-induced hyperalgesia in a study by Zhang-James et al. [13], which compared 32 tobacco users to 30 control subjects who had never used tobacco. Both male and female participants were included. Pain-tolerance assessment revealed a median Cold Pressor Test duration of 45 seconds among tobacco users versus 105 seconds in the control group; the diffe­rence was statistically significant.

The research conducted by Ditre et al. [3] investigated the effects of nicotine deprivation on experimental pain reactivity. A total of 165 18-to-65  year-old daily cigarette smokers of both sexes, who smoked not less than 15 cigarettes a day, were randomised into one of three groups: extended deprivation (12-24 hours of smoking abstinence), minimal deprivation (2 hours of abstinence) or continued smoking. Participants then underwent pain induction using topical capsaicin. The findings indicated that extended nicotine deprivation, compared to continued smoking, significantly increased capsaicin-induced pain intensity, neurogenic inflammation and hyperalgesia. Moreover, exploratory analyses suggested that pain sensitivity may increase with the duration of smoking abstinence. These results highlight the bidirectional relationship between pain and tobacco use, suggesting a positive feedback loop in which nicotine deprivation exacerbates pain thus reinforcing smoking behaviour.

Nicotine-induced oxidative stress in humans is well documented – the evidence base is the most extensive among all the mentioned substance classes, including data from a large, population-based cohort study [46]. Nevertheless, it has not yet been directly correlated to nicotine-induced hyperalgesia.

In conclusion, smoking and pain share a complex relationship wherein prolonged nicotine consumption often becomes a maladaptive coping strategy. Given the substantial public health and economic burden of tobacco use, future research should focus on the impact of both consistent smoking and smoking cessation on chronic pain outcomes. Furthermore, given the known effects of nicotine on pain modulation, it would be beneficial for future studies to investigate whether individuals dependent on opioids or benzodiazepines who also use nicotine may be at increased risk of withdrawal-associated hyperalgesia.

Cannabinoids

Cannabis remains the most widely used drug globally, with an estimated 15% prevalence among the EU population aged 15 to 34, including 2% reporting daily use [47] with pain being reported as the leading indication for medical cannabis use [48, 49].

Neurobiological mechanisms based on preclinical studies

Cannabinoids ease pain by engaging cannabinoid receptor 1 (CB1) on neurons and cannabinoid receptor 2 (CB2) on immune cells, downregulating nociceptive firing, reducing inflammatory mediators and even triggering peripheral opioid release for non-psychoactive relief [50-52]. CB1 signalling in hypothalamic-mesolimbic circuits boosts appetite and reward, while high tetrahydrocannabinol (THC) exposure can provoke euphoria but also anxiety and short-term memory loss [53, 54].

Studies on human populations

With these developments, there has been substantial growth in research examining cannabinoids as potential therapeutic agents for chronic pain [55, 56], with a major consensus report by the National Academies of Sciences, Engineering and Medicine in 2017, which by this time concluded that “substantial evidence” supports the effectiveness of cannabis use for the management of chronic pain in adults [48]. Nonetheless, a meta- analysis from a subsequent year reported that cannabinoids produced only small reductions in pain, without meaningful improvements in physical or emotional functioning. However, adverse events were substantially more common suggesting an unfavourable benefit–risk profile, making it unlikely that cannabinoids represent highly effective treatments for chronic noncancer pain [57]. 

Recent shifts in legislative frameworks and public perception have increased both medical and recreational availability of cannabis-based products, creating a necessity for critical evaluation of its potential risks, including the possibility of cannabis-induced hyperalgesia. Emerging stu­dies show that potentially, when THC levels fall, the diminished endocannabinoid tone unmasks sensitised pain pathways, lowering pain tolerance and yielding cannabis-induced hyperalgesia [13]. 

In a cross-sectional study by Bicket et al. [58] of 1,628 adults with chronic noncancer pain, 22% reported current cannabis use for pain management. Active cannabis use was associated with slightly higher pain intensity, greater pain interference and a higher burden of pain. The authors noted that the observation of the slightly-worse pain outcomes among cannabis users draws attention to the potential for adverse effects and related complications. Supporting the association between pain burden and cannabis use, Nugent et al. [59] observed that moderate pain was linked to a more than twofold increase in the odds of self-reported cannabis use, similarly pointing out the need for awareness of these trends when assessing the long-term treatment of chronic pain.

Campbell’s longitudinal study observed that individuals with chronic non-cancer pain who used cannabis for analgesia reported higher pain seve­rity scores over a four-year follow-up compared to non-users [11]. Furthermore, cannabis use did not correlate with reductions in prescribed opioid dosages nor facilitate opioid discontinuation. 

Research by Zhang-James et al. [13] provided similar results. Self-reported daily cannabis users “of lifelong drug use” tolerated the ice water for a median of 46s – about one minute less than substance-free controls (105s), with an even lower tolerance of 26s when cannabis and tobacco were combined, highlighting cannabis-associated hyper­algesia.

Finally, as with the other drug classes, some studies point to disturbed redox balance following cannabinoids’ prolonged use, with evidence based on larger clinical trials with human participants. Siwar et al. reported a significant redox imbalance in 100 hospitalised men with cannabis-use disorder, thiobarbituric acid-reactive substances (TBARS) and roughly doubled superoxide dismutase (SOD) activities, whereas reduced glutathione (GSH) and catalase (CAT) were markedly lower than in healthy controls, yet the study did not disclose the patients’ consumption frequency or dosing patterns [60]. Other clinical studies have likewise demonstrated the same shift towards oxidative stress [61, 62]. 

In conclusion, collectively, although earlier reports emphasised substantial evidence supporting the analgesic efficacy of cannabis for chronic pain, more recent meta-analyses and longitudinal investigations have increasingly focused on the consequences of prolonged use. These later studies suggest that long-term cannabinoid exposure is associated with modest clinical benefit, adverse events and, in some cohorts, a greater pain burden or reduced pain tolerance. As access to cannabis expands, a growing body of literature underscores the need for caution when considering cannabinoids as long-term therapeutic strategies for chronic non-cancer pain. 

With the wide global use of cannabis-based medicinal products (CBMP), there is a critical need for large-scale, longitudinal, methodologically rigorous clinical trials. These studies should stratify participants based on cannabis dosage, potency, route of administration and comorbid conditions to enable a more definitive understanding of the long-term somatic and psychological effects of cannabis use.

Stimulants

Psychostimulants such as cocaine and the amphetamines elevate extracellular monoamines through distinct interactions with presynaptic transporters: cocaine primarily blocks dopamine, norepinephrine and serotonin re-uptake, whereas amphetamine derivatives act as competitive substrates that trigger reverse transport and non- vesicular release [63-65]. The resulting surges of dopamine, norepinephrine, and serotonin activate the mesocorticolimbic reward circuit, driving reinforcement and addiction-related plasticity [66, 67].
In addition to shaping reward circuitry, activation of monoamine receptors in the periaqueductal gray–rostral ventromedial medulla descending analgesic pathways gates nociceptive input [53] before it ascends to higher centres, thereby potentially influencing pain perception. Likewise, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) flood the periaqueductal gray–rostral ventromedial medulla axis with serotonin, dopamine and noradrenaline, transiently recruiting the same descending analgesic circuit and thereby dampening incoming pain signals [68]. 

Although stimulant use is classically discussed in the context of reward and arousal, emerging evidence indicates that a subset of individuals, particularly those living with chronic non-cancer pain, use them to alleviate pain symptoms beyond recreational and performance motives [18, 69]. 

MDMA. Repeated MDMA intake has been shown to produce both acute and long-lasting hyperalgesia. This effect arises from an initial surge of serotonin (5-HT) via serotonin transporter (SERT), followed by withdrawal-related serotonin depletion and longer-term serotonergic neurotoxicity. These processes have been documented in both animal models and abstinent human users [70-72]. 

McCann et al. [70] focused on the broad phenomenon of MDMA’s serotonergic neurotoxicity. The study examined MDMA users after at least 2 weeks of drug abstinence. The trial measured indices of central 5-HT function, including nociceptive responses to ischemic pain. With lower levels of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (the major metabolite of 5-HT), elevated pain perception was observed. A subsequent trial [72] enrolled adults who reported at least 25 lifetime uses of MDMA and confirmed a minimum two-week period of total drug abstinence. Participants were admitted to a standardised measurement of pain. Pain threshold was controlled over multiple muscle groups and concluded responses for heat, pressure and cold stimuli, along with diffuse noxious inhibitory controls (DNIC) measurements. In comparison with age-matched controls who had never used MDMA, lower pressure pain thresholds, increased cold pain ratings and increased pain ratings during testing of DNIC were recorded, which strongly emphasised the role of MDMA in altering the pain perception of its users. Further confirmation came from the studies of O’Regan and Clow [71], where they described lower cold pain tolerance in MDMA users compared to polydrug users omitting MDMA. Several studies reported involvement of prolonged use of MDMA in the occurrence of oxidative stress and following neurotoxicity [73, 74] yet, to our knowledge, no research has studied both MDMA induced oxidative stress and hyperalgesia.

Amphetamine. Direct evidence regarding amphetamine-induced hyperalgesia remains very limited and speculative, with findings based on rodent trials. A notable example is the work of Zhu et al. [75] conducted on 48 male D3 receptor-modified and 48 wild-type mice after a 3-day acclimation. Allodynia was inflicted upon subjects, using both noxious heat and mechanical stimuli, with the amphetamine-exposed group displaying a significantly lower pain threshold than the controls. Results indicated that although the D3 receptor takes part in pain sensitivity, it does not contribute to the hyperalgesic effects of amphetamine. Importantly, as discussed at the end of this chapter, amphetamine exposure, similarly to MDMA, also elicits oxidative stress [76-78], which seems to be a central mecha­nism in amphetamine driven neurotoxicity [76]. 

Methamphetamine. Structural analogues of amphetamine like METH [76, 79], dextroamphetamine (D-amphetamine) [80] as well as mephedrone [81] have also been shown to evoke oxidative stress responses. According to current literature, methamphetamine appears to be the only amphetamine-class compound for which both oxidative stress and hyper­algesia have been investigated, yet due to such limited research, the evidence for this is speculative. In a very recent study by Kargar et al. [9], 35 male Wistar rats received two binge-like injections of METH (20 mg/kg i.p., 2 h apart). The results revealed that METH administration led to hyperalgesia, increased oxidative stress and impaired antioxidant defences in the periaqueductal gray. Importantly, the study directly correlated these coefficients, reporting a significant negative correlation between tail-flick latency and lipid peroxidation. 

Cocaine. Cocaine-induced hyperalgesia is more thoroughly investigated, with supporting human data. Compton et al. [82] examined 122 male current and former opioid and cocaine users aged 25-45, categorised by drug type and use status. In the cold pressor test (CPT), average immersion times ranged from 65 seconds (current opioid users) to 167 seconds (abstinent cocaine users). Although mean pain tolerance did not differ from normative data, the prevalence of pain intolerance was unexpectedly high, with a pain-sensitive to pain-tolerant ratio of 5.4 : 1, compared to 1 : 14 in normative samples. The study by Narendran et al. [83] on individuals with cocaine use disorder demonstrated an increase of nociceptive opioid peptide (NOP) receptors in brain regions involved in reward processing and stress regulation, mainly the midbrain, ventral striatum and cerebellum. In the review by Becker and Koob [84], the NOP increase was assumed to have originated following an adaptive decrease in nociceptin levels, which could, therefore, lead to changes in pain perception. Alas, without further research, these hypotheses remain insufficient to draw definitive conclusions. It is worth mentioning that, like previous compounds, cocaine also promotes the generation of oxidative stress [85, 86]. 

As a whole, recreational stimulants appear to interfere with normal neurotransmitter function, particularly serotonin and dopamine, leading to neurotoxicity, oxidative stress and impaired pain regulation, although most of the mechanisms have not yet been established and human evidence is limited. Future studies should incorporate substance-specific differentiation and longitudi­nal designs capable of distinguishing acute from chronic exposure, while directly evaluating whether stimulant use contributes to worsening of pre-
existing pain, a clinically relevant question that remains unresolved.

Benzodiazepines

Benzodiazepines (BZDs) act as positive allo­steric modulators of the gamma-aminobutyric acid type A (GABAA) receptor. Acutely, they exert anxiolytic, muscle-relaxing and sleep-inducing effects [87]; additionally, they dampen limbic and cortical reactivity to painful stimuli, lowering the anxiety-driven amplification of pain [8]. This manifests clinically as relief of muscle-spasm- related pain or event-associated distress [88-90]. Large-scale studies on patients with ongoing benzodiazepine treatment suggest that the analgesic properties of benzodiazepines may result from the alleviation of other pain-related symptoms like anxiety, insomnia and muscle spasms [88, 90, 91], showing little to no primary analgesic effects.

Prolonged BZD use is believed to drive homeostatic counter-regulation, as the brain attempts to restore balance. To offset sustained positive allo­steric modulation of GABAA receptors, neural circuits simultaneously downregulate GABAergic inhibition and heighten glutamate release [92, 93]. To date,
only a limited number of studies have addressed the phenomenon of hyperalgesia secondary to prolonged benzodiazepine use. Consequently, the mechanism of this phenomenon is based on very scarce data, yet clinical observations confirm that hyperalgesia is a prevalent symptom of BZD withdrawal syndrome, similarly to alcohol withdrawal. 

In the case series study, Heberlein et al. [94] also concluded that withdrawal from benzodiazepines is accompanied by increased glutaminergic neurotransmission, consequently also by increased nerve growth factor (NGF), a mediator that sensitises nociceptors and promotes central sensitisation. Moreover, with the cessation of use, hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation was observed in the study by Wichniak et al. [95], conducted on a group of 14 patients diagnosed with major depressive episode and medicated with benzodiazepines. In this trial, the severity of BZD withdrawal correlated with HPA over-activity, a state known to exacerbate stress-induced hyperalgesia. 

A recent online survey conducted by Lape et al. [96] on 306 adults with chronic musculoskeletal pain and a current benzodiazepine prescription found that intensity of pain was positively correlated with benzodiazepine use frequency, dependence severity and the likelihood of benzo­-
diazepine misuse behaviours. Of all the partici­pants, 45% reported that benzodiazepines had been prescribed for pain and 56% endorsed pain as a symptom for which they sought relief when taking benzodiazepines. 

Benzodiazepine-specific symptoms of hyperalgesia are yet to be defined and quantified in controlled human studies. Thus far, in the study by Gerra et al. [97], conducted with 50 adults with a diagnosis of benzodiazepine dependence according to DSM-IV criteria, the assessment of benzodiazepine withdrawal included hyperalgesia sensations like muscle or stomach cramps, headache, sore eyes and pins and needles – reported by patients as burning or electric-like pain – as well as heightened sensitivity to touch. However, because the authors reported only compound withdrawal scores and did not analyse each symptom separately, it is impossible to determine which of those pain-related issues occurred and if so, how often. 

Animal model and in vitro studies suggest that chronic use of benzodiazepines could push the redox balance toward oxidation [98-100] (as previously mentioned, hypothesised by us to be a potential factor of secondary hyperalgesia), yet human studies are very limited. In a six-month study of 80 adults with anxiety disorders, nightly intake of 0.5 mg of clonazepam resulted in a significant increase in oxidative stress [101]. 

Overall, a relationship between prolonged benzodiazepine intake and altered pain perception seems very likely; nonetheless, the current state of research on this subject remains insufficient, including a lack of data on physiological symptoms. While survey data suggest that a subset of patients take benzodiazepines to obtain pain relief, there is currently no direct longitudinal or experimental evidence establishing that benzodiazepine use exacerbates pre-existing pain. 

Despite international guidelines recommending “short-term” (commonly up to 4 weeks) use of benzodiazepines [102], real-world practice often drifts toward chronic use. In a cohort study by Gerlach et al. [103], nearly one-third of elder adults newly prescribed a benzodiazepine transitioned to long-term use within 12 months and in Finland, 34% of working-age and 55% of older new users progressed to long-term use (≥ 180 consecutive days) [104]. Given these rates, future investigation towards adverse consequences of chronic benzodiazepine therapy should be a research priority.

Hypnotics (Z-drugs)

Z-drugs such as zolpidem, zaleplon and zopiclone are rapid-onset, short half-life hypnotics. Zolpidem and zaleplon selectively potentiate α1 GABAA receptors, with studies confirming that this mechanism underpins their sleep-promoting mode of action. Chronic nightly dosing, however, decreases expression of mRNA encoding the α1 GABAA receptor subunit. It is crucial to emphasise that the only published mention of “hyperalgesia” during Z-drugs withdrawal comes from a review [105] citing a dated paper Pelissolo and Bisserbe [106], that borrowed the term from benzodiazepine literature without actual data on Z-drugs themselves. Accordingly, all subsequent considerations of potential Z-drug-induced hyper­algesia and its mechanisms are necessarily speculative, though in our view they offer a valuable basis for potential future investigations. 

Based on existing research, we hypothesise that the previously mentioned mechanism, which decreases α1 GABAA receptors in long-term daily users, could potentially be responsible for secondary hyperalgesia. The first aspect of this correlation, a link between the administration of Z-drugs and a reduction in GABAA receptor α1 subunit expression, has been demonstrated in several studies. Holt et al. [107] showed that in the rodent cortex, zolpidem treatment significantly increased α4 and β1 GABAA receptor subunit mRNA levels after
7 days of zolpidem treatment but decreased α1 subunit mRNA after 14 days. In a study by Auta et al. [108] long-term zolpidem treatment reduced the expression of mRNA encoding the α1 GABAA receptor subunit in the prefrontal cortex by 20%. Moreover, a trial of Follesa et al. [109] found that discontinuing treatment with either zaleplon or zolpidem led to a decrease in the amounts of α1, β2, γ2L, and γ2S subunit mRNAs, as well as an increase in that of the β1 subunit mRNA.

Concurrently, two independent stress and injury models suggested that decreased spinal
GABAergic activity can cause hyperalgesia in rodents, leaving a possibility for the hyperalgesic effect of Z-drugs [110, 111]. A study by Wu et al. [110] found that a single prolonged stress exacerbated the postoperative pain in rodents. Simultaneously, their lumbar spinal cord contained reduced glutamic acid decarboxylase-65, glutamic acid decarboxylase-67, GABAA receptor α1 subunit, and GABAA receptor γ2 subunit. The same link was present in a study by Hadadi et al. [111] where a treatment with curcumin 100 and 200 mg/kg significantly improved GABAA receptor after a spinal cord injury, which was connected to a significant increase in pain threshold. Even though these studies were conducted on relatively small sample sizes (3-8 animals per group; 40 in total respectively), it is noteworthy that each yielded statistically significant results. 

We speculate that an alternative pathway through which zolpidem may lead to secondary hyperalgesia involves paradoxical sleep fragmentation, although this relationship has not been thoroughly explored. Existing reports suggest a link between all Z-drug use and sleep instability [112-115]. In turn, several clinical studies have addressed the connection between sleep deprivation and lower pain threshold [116-118]. An additional meta-analysis of 61,000 participants indicated that any decline in sleep quality or quantity was asso­ciated with a two-to-three-fold higher risk of developing a painful condition [119]. 

Another potential pathway that has yet to be confirmed, by which Z-drugs may induce hyperalgesia, is the upregulation of oxidative stress,  a process that has been demonstrated in preclinical trials [120, 121]. 

In conclusion, α1 GABAA receptor down-regu­lation, sleep instability, and disturbed redox balance are biologically coherent avenues through which Z-drugs might foster hyperalgesia. Yet, to date, no study has linked Z-drug misuse with objective hyperalgesic effects. Until trials directly measure pain thresholds before and after chronic Z-drug exposure, hyperalgesia remains a theoretical rather than an evidence-based risk. Thus, rigorously controlled studies are urgently needed.

■ Treatment

Current focus – abstinence over pain

Today, therapy for patients affected by SUDs other than opioid- and alcohol-use disorders typi­cally does not include regimens targeted specifically at pain relief; the current studies are mainly directed towards pharmacological management of dependence and withdrawal symptoms [122]. A review of nearly 1,000 residential SUD programmes found that only 2.9% offered any chro­nic pain-specific programme [123]. Since, for most of the substances discussed, their potential to cause hyperalgesia remains a partially substantiated theory, appropriate treatment regimens addressing this issue have not yet been established. Below, we present an overview of current, still limited, perspectives on the treatment of hyperalgesia in patients affected by SUDs.

Substance-specific pharmacological approaches

Several potential therapeutic agents have been investigated for the treatment of nicotine withdrawal, which is frequently associated with hyperalgesia, with promising evidence supporting the need for further research. A meta-analysis of 20 randomised controlled trials by Gou et al. [124] concluded that varenicline and bupro­pion interventions significantly influenced smoking cessation in comparison with placebo, with the best results in combined therapy, yet their potential role in the therapy of hyperalgesia induced by nicotine withdrawal is not well researched, though some rodent studies show promising results. A pre-clinical study by Damaj et al. [125] demonstrated that bupropion and, more potently, its (2S,3S)-hydroxybupropion metabolite rapidly normalised withdrawal-related thermal hyperalgesia in mice, indicating that this metabolite may be chiefly responsible for bupropion’s anti-withdrawal analgesic efficacy. In a mouse model study by Bagdas et al. [42], varenicline yielded promising results, similarly reversing hyperalgesia secondary to nicotine withdrawal.

Treatment of withdrawal, including pain sym­ptoms occurring after discontinuing benzodiazepines, is well documented and offers incorporation of flumazenil. This agent binds the benzodiazepine site on GABAA receptors, acting in small doses as a weak partial agonist [97, 126, 127]. The previously mentioned clinical study by Gerra et al. [97] randomised 50 benzodiazepine-dependent patients and showed that the 20 participants who received intravenous flumazenil (1 mg twice daily for 8 days), along with only three night-time micro-doses of oxazepam, revealed a significant drop in withdrawal scores on a 33-item self-report scale. This scale included pain-related items such as aches or pains, muscle or stomach cramps, headachy and muscles twitching. Benini et al. [126] treated 14 high-dose benzodiazepine users with a 7-day continuous subcutaneous flumazenil infusion (1 mg/day) delivered by an elastomeric pump, while clonazepam was tapered nightly. Withdrawal was tracked with the 33-item Benzodiazepine Withdrawal Scale (BWS); mean scores fell from 26.4 at admission to 17.7 at day 7. BWS improved significantly during the flumazenil treatment in all subjects. Hulse et al. [128] gave 23 benzo­diazepine-dependent patients a 96-h subcutaneous flumazenil infusion (~4 mg/day ± 20%) plus minimal oxazepam. The Benzodiazepine Withdrawal CIWA-B Scale, including fatigue, headache, and muscle pain, dropped from 19.9 ± 3.3 (day 2) to 15.6 ± 2.8 (day 3). Among 13 respondents, 75% rated the infusion extremely comfortable, and 85% would repeat it. Importantly, both studies did not present any pain-specific endpoints; only the total BWS scores were reported. Regardless of the promising results as of 2021, therapies using flumazenil infusions were available at only five clinics worldwide [126]. 

Studies evaluating therapeutic, pharmacologi­cal approaches targeting hyperalgesia secondary to cannabinoids, stimulants and Z-drugs use remain to be undertaken.

Oxidative stress as a therapeutic target

Emerging evidence based on pre-clinical studies suggests that the attenuation of oxidative stress may represent a viable strategy for mitigating hyperalgesia associated with opioid use, given the shared involvement of oxidative and nociceptive pathways [129-132]. However, to our knowledge, data exploring whether oxidative stress modulation can alleviate hyperalgesia linked to other psychoactive substances is extremely limited. Notably, in a recent study on methampheta­mine treated rats, administration of alpha-lipoic acid increased activity of antioxidant enzymes (catalase and superoxide dismutase) in the periaque­ductal gray, thereby diminishing oxidative stress and decreasing hyperalgesia as well as anxiety-like beha­viours resulting from acute methamphetamine administration [133].

Behavioural and integrated approaches

Integrating pharmacotherapy with a psychosocial intervention is known to enhance outcomes in individuals with SUDs [134, 135]. Behavioural therapies, unlike pharmacotherapy, can be applied across a range of SUDs with fairly little adaptation [136]. A recent clinical study conducted by Ilgen et al. [137] examined the efficacy of an integrated behavioural pain management intervention (Improving Pain During Addiction Treatment, ImPAT) for 264 men and 246 women receiving residential treatment for SUDs including drug,
alcohol, and/or opioid medication misuse, and subsequently examined the results separately by sex.
Over follow-up assessments at 3, 6, and 12 months, this type of intervention was associated with better pain-related outcomes, primarily pain tolerance in men and pain intensity in women. 

Patients with SUDs are especially prone to inadequate treatment: clinician distrust, fear of diversion and regulatory pressures can all limit access to effective pain medication. When pain remains undertreated, “pseudo-addictive” behaviours like frequent dose escalations, medication hoarding or drug-seeking may emerge and overlap with withdrawal symptoms, mimicking them while being driven primarily by uncontrolled pain [138].

Clinical barriers and structural challenges

Because the SUD population is heterogeneous, treatment programmes range from the single-agent pharmacotherapies to the multimodal behavioural or psychosocial. Importantly, success is still typically judged by abstinence or a clinically meaningful reduction in use, disregarding the issue of pain symptoms [136]. Overall, studies on benzodiazepines and nicotine are very scarce and preliminary, involving only small numbers of participants. No studies directly address pain treatment in people who use cannabinoids or stimulants. We believe this situation calls for the implementation of targeted therapeutic strategies specifically addressing pain management.

■ Discussion and Conclusions 

Pain dysregulation as a transdiagnostic feature of SUDs

This review aimed to synthesise and systema­tise the current state of knowledge on pain dysregulation associated with problematic substance use. This objective was motivated by emerging evidence across pre-clinical and human studies, showcasing that pain sensitivity is not a distinctive complication of opioid or alcohol use alone but a transdiagnostic feature of SUDs. Long-term exposure to nicotine, cannabinoids, stimulants, benzodiazepines and non-benzodiazepine hypnotics fosters a shift from acute antinociception to a maladaptive state characterised by lowered nociceptive thresholds and heightened affective distress. 

Furthermore, we hypothesise that all of the substance classes seem to possess the potential to induce hyperalgesia through the enhancement of oxidative stress pathways.

To the best of our knowledge, this is one of the first papers to provide a comprehensive overview of the impact of SUDs on alterations in pain thresholds beyond opioid and alcohol addiction.

Substance-specific patterns of hyperalgesia

A consistent pattern emerges despite the strength of empirical support varying across substance classes. Nicotine presents a clear picture: propensity-weighted analyses and deprivation studies show that smokers experience greater baseline pain and that abstinence precipitates capsaicin-evoked hyperalgesia, illustrating a potent driver of relapse [3, 39]. 

Evidence for cannabis is quite consistent. Expe­rimental pain models indicate reduced pain tolerance among chronic users while longitudinal cohorts report higher pain severity in patients using cannabis for analgesia, and mechanistic findings propose that declining THC levels may unmask sensitised nociceptive pathways. Nevertheless, current evidence is mostly observational and insufficient to establish whether cannabis exposure directly worsens pre-existing pain.

Prolonged stimulant use is associated with serotonergic and dopaminergic neurotoxicity, reduced tolerance to thermal and pressure pain, and decreased nociceptin levels in reward-stress hubs of abstinent cocaine users [83]. To this date, only one study directly links oxidative stress induced by an amphetamine derivative to hyperalgesia [9]. 

Evidence for benzodiazepine-linked hyperalgesia is scarce yet coherent: human withdrawal micro-studies reveal glutamatergic surges, NGF release and HPA-axis over-activity, all of which are pronociceptive, while case studies describe burning, electric-shock-like pain [94, 97]. Greater pain intensity in chronic pain patients was associated with higher-risk benzodiazepine use patterns, though causality could not be established [96]. Nevertheless, small cohort samples and composite withdrawal scores remain a substantial limitation. 

Evidence supporting the role of Z-drugs in mo­du­lating hyperalgesia remains predominantly preclinical, limited and largely circumstantial. Available findings suggest that these agents may induce α1 GABAA receptor downregulation [107-109] and contribute to sleep fragmentation [112-114]. Both mechanisms have been independently associated with increased pain sensitivity and hyperalgesia [110, 111, 116-118]; however, a direct causal link between the use of hypnotic agents and hyperalgesia has not yet been conclusively established.

Clinical implications

Individuals with persistent pain face a greater risk of developing SUDs, and those who already have SUDs commonly report persistent and intense pain [96, 139]. Consequently, patients entering treatment for SUDs often report experiencing pain, which has been proven to reduce treatment outcomes, increase the chances of relapse, and lead to heavier substance use after discharge [140, 141]. Importantly, pain catastrophising, negative urgency and strong beliefs that substances relieve pain can further intensify vulnerability to relapse [12, 14, 19].

Despite this close linkage, only a minority of residential services offer pain-specific interventions, perpetuating unmet needs. This review highlights emerging pharmacotherapies – varenicline and bupropion for tobacco, flumazenil for benzodiazepines and alpha lipoic acid for methamphetamines as well as behavioural approaches like cognitive-behavioural therapy and contingency management, which show moderate efficacy when integrated.

This outlook is intended to draw attention to the possible consequences of hyperalgesia associated with various SUDs. It serves as a reminder to clinicians to consider implementing an effective pain management strategy as a supportive means in the treatment of addiction. It adds credibility to the potential pain complaints of patients affected by SUDs, which could enable them to access the pain medications they genuinely need and prevent excessive pain from becoming their reason for relapse. With a growing body of evidence on the co-occurrence of chronic pain and addiction, breaking the self-reinforcing cycle of repeatedly using substances to manage ever-increasing discomfort is crucial to improve recovery rates. Addressing both of these issues could also meaningfully improve the patient–physician relationship, considerably contributing to better overall treatment adherence.

Limitations

Limitations of the current evidence base. A substantial proportion of available data, especially concerning stimulants and benzodiazepines, still derives from preclinical animal models, limiting direct translational applicability to human pathophysiology. Human studies are frequently cross-sectional and involve small cohort samples. Heterogeneity in substance exposure patterns, such as variability in dose, duration, route of administration, and polysubstance use, complicates interpretation and clear dose-response analyses. Finally, longitudinal clinical trials capable of establishing causal inference remain scarce. 

Limitations of the present review. This review adopts a narrative and integrative approach rather than a formal meta-analytic synthesis, which limits quantitative comparison of effect sizes across substances. Despite efforts to provide a balanced synthesis, the narrative design may be vulnerable to selection bias in study inclusion and interpretation. By design, it excludes opioid and alcohol-induced hyperalgesia to focus on less-studied substances, which may limit direct comparability with the broader SUD literature. The heterogeneity of included study designs and outcome measures limits the ability to standardise conclusions across substance classes.

Future research directions

Large-scale longitudinal and randomised controlled trials should aim to accurately identify the prevalence and magnitude of substance-induced hyperalgesia across multiple substance classes. It is crucial to establish temporality and causality between substance exposure, withdrawal and changes in pain sensitivity, ideally using Harmonised Quantitative Sensory Testing (QST) protocols across cohorts. Trials should characte­rise exposure with greater precision (dose, potency, route, duration and polysubstance patterns).
It would also be valuable for future research to explore whether chronic substance-induced oxidative stress contributes to the emergence or intensification of pain and, long-term sleep disturbances in the case of Z-drugs and benzodiazepines as already established in the literature, may be
associated with increased pain vulnerability.

Finally, further research across substance classes is needed to identify effective pharmacological strategies as well as the impact of pain management on the clinical outcomes of dependence treatment.

Ultimately, this review seeks to highlight that pain appears to be a potentially significant factor in chronic substance use. Addressing pain management may meaningfully influence treatment success and relapse prevention, leading to more effective and sustainable care for individuals with substance use disorders, gradually eliminating factors that contribute to the chronic nature of dependence.

Conflict of interest/Konflikt interesów

None declared./Nie występuje. 

Financial support/Finansowanie

None declared./Nie zadeklarowano. 

Ethics/Etyka

The work described in this article has been carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) on medical research involving human subjects, Uniform Requirements for manuscripts submitted to biomedical journals and the ethical principles defined in the Farmington Consensus of 1997.

Treści przedstawione w pracy są zgodne z zasadami Deklaracji Helsińskiej odnoszącymi się do badań z udziałem ludzi, ujednoliconymi wymaganiami dla czasopism biomedycznych oraz z zasadami etycznymi określonymi w Porozumieniu z Farmington w 1997 roku.

References/Piśmiennictwo