The Endogenous Opioid System (EOS)

The endogenous opioid system (EOS) has been implicated in the pathogenesis and maintenance of NSSI, largely due to its role in the mechanisms of pain analgesia; reinforcement and reward; the modulation of affect and stress responses; and also addiction (Ribeiro, Kennedy, Smith, Stohler, & Zubieta, 2005; Sandman & Kemp, 2011; Sher & Stanley, 2008). Endogenous opioids and their receptors are opiate-like

97 substances that are naturally produced and reside in the central and peripheral nervous systems (Kirtley, O’Carroll, & O’Connor, 2015; Koneru, Satyanarayana, & Rizwan, 2009; Ribeiro et al., 2005). Since the mid-1970s four primary classes of opioid peptides have been identified: endorphins, enkephalins, dynorphins, and endomorphins. Each of these opioid peptides ligand to three distinct classes of G-protein receptors: labelled mu (μ), delta (δ) and kappa (κ) (Benarroch, 2012; Bloom & Holly, 2011; Ribeiro et al., 2005). The complex opioid signaling pathways and their associated receptors proliferate many areas of the brain, and the central and peripheral nervous systems (Koneru et al., 2009). Their physiological effects are dependent upon which receptor is activated by which peptide (Osuch & Payne, 2008).

Stress, pain, exercise and sexual activity all stimulate the release of endorphins, which produce analgesic and euphoric effects whilst simultaneously decreasing the level of anxiety experienced in the body (Koneru et al., 2009). Alternatively, whilst still heavily involved in pain regulation, dynorphins function quite differently and can generate depersonalization, derealisation, and dysphoria (Bandelow, Schmahl, Falkai, & Wedekind, 2010; Koneru et al., 2009). Research indicates that physical pain and

emotional distress are modulated by similar regions in the brain and there is

considerable overlap amongst these two processes (Bresin & Gordon, 2013). Given the known relationship between the EOS in the regulation of pain and affect, the application to NSSI appears somewhat intuitive and parsimonious (Bresin & Gordon, 2013; Ribeiro et al., 2005).

Evidence supporting the potential role of the EOS in NSSI has been derived from four main sources: the pain hypothesis, the addiction hypothesis, trials of

98 psychopharmacological opioid antagonists, and lower levels of endogenous opioids in the plasma and cerebrospinal fluid of self-injurers.

5.4.1.1 The Pain Hypothesis

Primarily, numerous reports of pain analgesia during the act of NSSI implicates the EOS (refer to section 7.7.4 for further discussion on pain analgesia in NSSI: Bohus et al., 2000; Claes, Vandereycken, & Vertommen, 2006; Franklin, Hessel, & Prinstein, 2011; Glenn, Michel, Frankin, Hooley & Nock, 2014; Hooley et al., 2010). Often referred to as the pain hypothesis in the literature, the theory underpinning this

hypothesis suggests that individuals who self-injure possess a diminished sensitivity to pain, either due to greater levels of endogenous opioids, and/or hypersensitive opioid receptors (Bandelow et al., 2010; Bloom & Holly, 2011; Grossman & Siever, 2001; Sandman & Kemp, 2011). The act of self-injury is then employed as a method of stimulation to interrupt and stop dissociation, or feelings of numbness and

depersonalisation, which may have been triggered by interpersonal or environmental stressors (Grossman & Siever, 2001; Sandman & Hetrick, 1995).

5.4.1.2 The Addiction Hypothesis

Secondly, reports of the addictive properties that NSSI wields, adds further support that the EOS proffers some significance in the maintenance of self-injurious behaviours (Grossman & Siever, 2001; Nixon, Cloutier, & Aggarwal, 2002; Plener et al., 2013; Sandman & Kemp, 2011). The addiction hypothesis is based on addiction studies and postulates that the EOS has been chronically overstimulated by repeated

99 self-injurious behaviour in an attempt to alleviate negative affect. Consequently, the individual develops a tolerance to the heightened opiatergic tone, through this habitual overstimulation of endogenous opioids. They then periodically suffer from a withdrawal response. This stimulates a desire for further endogenous reward, which they have learnt via repetition to activate through the physical act of self-injury (Grossman & Siever, 2001; Osuch & Payne, 2008; Sandman & Kemp, 2011). According to Grossman and Siever (2001), additional support for the addiction hypothesis is found in reports that individuals who engage in repetitive NSSI experience strong urges to self-injure; they demonstrate a need to increase the severity of their NSSI; and they have great difficulty terminating their NSSI. Bandelow et al. (2010) contended that as endorphins are only released when actual tissue damage occurs, cutting is a far more effective method of obtaining a biochemical reward, than self-injurious methods that do not penetrate or damage the skin (pinching, banging or hitting oneself & interference with wound healing). This may accentuate why cutting has consistently been reported as the most common method of NSSI (Cawood & Huprich, 2011; Heath et al., 2008; Klonsky, 2007, 2011; Martin, Swannell, Hazell, et al., 2010; Nixon et al., 2008). Furthermore, Bandelow et al. suggested that this could also explain why replacing cutting with non- injurious alternatives that do not result in bleeding (e.g., holding ice cubes against the skin or snapping elastic bands around the wrist), fail to have the same therapeutic effect as self-injurious behaviours that enact tissue damage.

5.4.1.2.1 Psychopharmacological Trials of Opioid Antagonists

The partial success of psychopharmacological trials of opioid antagonists (i.e., naltrexone hydrochloride and naloxone) to reduce self-injurious behaviours in

100 developmental disorders (Barrett, Feinstein, & Hole, 1989; Sandman & Kemp, 2011; Sandman, Touchette, Lenjavi, Marion, & Chicz-DeMet, 2003) and in individuals diagnosed with BPD (McGee, 1997; Roth, Ostroff, & Hoffman, 1996; Sonne, Rubey, Brady, Malcolm, & Morris, 1996) adds further support to the addiction hypothesis, and an opioid release during NSSI. Naltrexone is an oral medication originally administered to block physical dependence in substance abusers (Walsh, 2006). Naltrexone is thought to be effective in reducing self-injurious behaviour as it attenuates the endogenous reinforcement experienced after the act of NSSI, and the behaviour decreases as it is no longer biochemically rewarding (Bandelow et al., 2010; Bresin & Gordon, 2013). However, empirical results on the use of opioid antagonists have been mixed to date in studies of individuals with developmental disorders, and clinical samples. Therefore, they are yet to warrant application in nonclinical trials (Bandelow et al., 2010; Bloom & Holly, 2011; Plener & Libal, 2014; Sandman & Kemp, 2011; Symons, Thompson, & Rodriguez, 2004).

5.4.1.3 Lower Levels of Endogenous Opioids

Finally, several studies have found altered levels of endogenous opioids in the plasma (Coid, Allolio, & Rees, 1983) or cerebral spinal fluid (CSF: Stanley, Sher, Wilson, Ekman, Huang, & Mann, 2010) of individuals who engage in NSSI, when compared to non-injurers in clinical and developmental disorders. However, it is not known whether the lower levels of β-endorphin and met-enkephalin that Stanley et al. (2010) found in a sample of psychiatric patients diagnosed with BPD, would also be found in nonclinical samples of individuals who self-injure. Furthermore, there appears to be a discrepancy between the levels of endogenous opioids obtained via plasma using

101 venipuncture (Coid et al., 1983; Weizman et al., 1988), or CSF using a lumbar puncture (Stanley et al., 2010), significantly confounding cross study comparisons. There is some evidence to indicate that plasma sampling provides a more dynamic measure of

endogenous opioids than CSF, which appears to reflect a more stable or baseline measure of endogenous opioids (Kirtley et al., 2015).

Despite the identified relationship between pain and the EOS, this is a relatively new avenue for exploration in NSSI and only a few studies have been undertaken to date (Stanley et al., 2010). As such, there are a number of significant limitations with the extant research, aside from those already addressed. All of these studies are based on clinical samples, predominantly in individuals diagnosed with BPD (Coid et al., 1983; Stanley et al., 2010); or in individuals with developmental disorders (Weizman, Gil-Ad, Dick, Tyano, Szekely, & Laron, 1988). The sample sizes in these studies are also small, further limiting generalization (Coid et al., 1983; Stanley et al., 2010), and there are considerable differences in their methodology. Whilst converging avenues of evidence point to the involvement of the EOS, future studies need to investigate the role that EOS plays in the neurobiological aetiology of NSSI (Sher & Stanley, 2009).