Dear Editor,

We would like to thank the Correspondents – Marcin P. Nowak and Nastazja Bielicka [1] – for their careful reading of our review [2]. We are grateful for the opportunity to respond and to clarify our position.

First, we agree that there is no single, common psychoactive-substances effect on redox balance. Our review presented substance specific neuroadap­tations as the primary drivers of hyperalgesia and proposed the contribution of oxidative stress only as a plausible hypothesis, as stated in the abstract. In Table I, where the neuroadaptive mechanisms underlying hyperalgesia are summarised, we flagged every oxidative stress pathway with an asterisk, pointing out that while the link is indirect, the underlying mechanisms have independently been shown to drive pain sensitisation; we propose this correlation as a hypothesis based on existing data. Finally, we’ve stated in the discussion that to our knowledge, data exploring whether oxidative stress modulation can alleviate hyperalgesia linked to other psychoactive substances is extremely limited [2].

We would also like to draw attention to the dose- and context-dependent nature of redox effects, which we believe helps clarify this point further. Cannabinoids, for instance, may exert anti­oxidant effects acutely, yet chronic cannabis-use disorder is associated with a net pro-oxidant shift [3, 4].
Similarly, while the Correspondents rightly note antioxidant properties of benzodiazepines in some studies, including the one they cite [5], it is worth noting that this refers to acute administration: animal models and in vitro studies consistently demonstrate pro-oxidative effects following chronic benzodiazepine use, as we discussed in our review [6-8].
Regarding Z-drugs, we fully acknowledge that the evidence for oxidative stress secondary to chronic use remains weak and largely preclinical, as we explicitly stated. In this context, we would gently note that the antioxidant effect of zolpidem reported in the study cited by the Correspondents [9] was likewise observed following a single acute dose and therefore does not, in our view, contradict the hypo­thesis we proposed for chronic exposure.

Further, we have to disagree with the premise that hyperalgesia typically occurs not while taking substances, but after their discontinuation – even in case of the opioid model. It has been consistently shown that opioid-induced hyperalgesia (OIH) develops during ongoing chronic opioid exposure, not merely as a withdrawal phenomenon [10-12]. Perhaps most notably, the review by Marchette et al. [13], evoked by Correspondent, similarly acknowledged that hyper­algesia is a common response to chronic
opioid use in humans, with tole­rance and even signreversal occurring in the pre­sence of opioids [13].

Likewise, current smokers report a greater pain burden during ongoing use [14], and chronic daily cannabis users show significantly reduced experimental pain tolerance [15]; therefore there is a during-use component. Where hyperalgesia does peak in withdrawal, it still does not exonerate a redox contribution, as withdrawal has been shown itself to be a pro-oxidant state [16-18]. We acknowledge that human literature remains small and not wholly consistent; nonetheless, a recent meta-analysis of 61 studies confirms increased oxi­dant and reduced antioxidant markers across sti­mulants, nicotine, cannabis, alcohol, opioids, inha­lants and polysubstance users with substance-use disorder (SUD) [19].

We do not dispute the opponent-process account, which we ourselves invoked in our description of the self-reinforcing cycle underlying substance-induced hyperalgesia [2], nor the allostatic framework, which we referenced in the context of alcohol-induced pain dysregulation [20]. Further, we agree that the dynorphin/κ-opioid receptor (KOR) system represents a well-established mecha­nism of hyperalgesia in opioid and alcohol dependence, and it has been studied to play a role in dependence on other psychoactive substance classes as well. Nevertheless, its direct correlation to hyperalgesia in this regard remains to be demonstrated [13].

As we stated explicitly, oxidative stress was proposed only as a potential contributor to pain vulnerability, not as a primary mechanism, and certainly not as one that supplants neuroadaptation. In our view, it is not a competing but contributing hypothesis.

The opponent-process framework operates at the systems level, where chronic substance exposure drives progressive hypersensitisation of nociceptive circuitry through reward, stress, anti-stress systems and neuroadaptation [20]. Oxidative stress operates at the cellular level: it represents one candidate mechanism through which this circuit-level sensitisation may be reinforced, namely, through reactive-oxygen-species-mediated NMDA-receptor phosphorylation, spinal microglial activation and attenuation of GABAergic inhibitory tone [21, 22]. We therefore read the two frameworks as convergent levels of a single allostatic cascade rather than as rivals. We stress, however, that the cellular cascade linking oxidative stress to central sensitisation is established primarily in rodent models [21, 22], with only correlational human biomarker support to date.

Finally, we believe the proposed test in beha­vioural addictions is important, and we agree with its logic. However, behavioural addictions are not redox-neutral, since sleep deprivation [23] and sedentary lifestyle [24], which often accompany them independently, have been linked to increased oxidative stress [25-27], so even a posi­tive Quantitative Sensory Testing (QST) finding would not cleanly isolate neuroadaptation from redox mecha­nisms. A decisive test would require Harmonised Quantitative Sensory Testing in behavioural-addiction cohorts, consistent with the longitudinal design we called for in the review [2], with additional control for the confounders noted above. Until these studies are conducted, as the Correspondents rightly conclude, we remain largely in the realm of hypothesis.

We are grateful for this exchange. We believe that confirming or excluding any clinically meaningful role of oxidative stress in substance-related hyperalgesia would have direct therapeutic implications. If redox disturbance proves to be a contributing factor, antioxidant-based interventions could be integrated into addiction treatment as a supportive strategy for managing pain and, potentially, reducing relapse vulnerability. We would like to thank the Correspondents and the Editor for the opportunity to continue this dialogue.

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