Dear Editor,

“A comprehensive review of altered pain regulation in problematic substance use” by Winogradow et al. [1] published in Alcoholism and Drug Addiction is a very interesting and meaningful work that considers the problem of hyperalgesia observed in patients with substance use disorder (SUD). The authors address an important, yet previously underappreciated issue, while focusing on other addictions than alcohol and opioids not hitherto described in the literature.

The authors hypothesise that, in addiction, pain-perception disorders result primarily from oxidative stress caused by the intake of substances that disrupt the body’s redox balance, which is associated with inflammation. The relationship between oxidative stress and inflammation has been confirmed in the etiopathogenesis of many diseases, including those related to the central nervous system (CNS) [2] and pain is one of the symptoms of inflammation. While we appreciate the publication, we would like to raise some doubts about this interesting hypothesis.

First of all, most studies confirm oxidative stress when using psychoactive substances like tobacco [3], cocaine [4], methamphetamine [5] and stimulants in general [6]. On the other hand, some of them like cannabinoids [7], benzodiazepines [8] and Z-drugs also have antioxidant properties [9]. Therefore it is difficult to speak of a single, common effect of psychoactive substances on the body’s redox balance.

Secondly, the effects mentioned above result from the pro or antioxidant activity of the psychoactive-substance molecules themselves or from their interaction with receptors. As a result of this described mechanism, one would expect these effects to occur while taking these substances. However, hyperalgesia and allodynia typically occur not while taking the substances, but after their discontinuation, not only in the case of substances discussed in this article, but also following opioid use [10].

There is a much simpler hypothesis explaining addiction-related hyperalgesia and allodynia: it stems from changes in brain neurotransmitter function resulting from the addiction itself.
The euphoric effect of the substances mentioned above is associated with a reduction in pain perception. The opponent process theory (OPT) [11] states that CNS mechanisms oppose hedonic states, reducing hedonic-feeling intensity. Accordingly, long-term substance use leads to pain-perception system compensatory hypersensitisation and, as a result, to increased sensitivity to pain.

The well-documented disturbances in pain perception following opioid withdrawal are explained by neuromodulation via dynorphins – endogenous peptides that activate κ-opioid receptors [10].
Morphine withdrawal increases dynorphin secretion [12], although a decrease is observed immediately after administration [13]. Dynorphin secretion changes have been also observed in alcohol dependence [14], stimulants [15], nicotine [16] and THC [17].

A test that would help distinguish between these hypotheses would be a study of pain perception in individuals with behavioural addictions. Hyperalgesia following cessation of the addictive activity would indicate a mechanism related to addiction and OPT, while its absence would point to oxidative stress. Unfortunately, the topic of behavioural addictions, particularly due to internet addiction, which has recently gained increasing attention, is still poorly understood and difficult to diagnose (as also discussed in “Alcoholism and Drug Addiction” [18, 19]).

Currently, there is a lack of this kind of study (search in the PubMed database using the keyword combinations “behavioural addiction”, “gaming disorder”, “internet disorder”, “hyperalgesia” and “pain”) although it is believed that the sensation of pain decreases during euphoric activity. Until these are conducted, we remain in the realm of hypotheses.

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