Comorbid chronic pain and opioid use disorder: literature review and potential treatment innovations

Abstract

Chronic pain (CP) and opioid use disorder (OUD) remain challenging complex public health concerns. This is an updated review on the relationship between CP and OUD and the use of stepped care models for assessment and management of this vulnerable population. A literature search was conducted from 2008 to the present in PubMed, Embase, and PsycInfo using the terms pain or chronic pain and opioid-related disorders, opiate, methadone, buprenorphine, naltrexone, opioid abuse, opioid misuse, opioid dependen*, heroin addict, heroin abuse, heroin misuse, heroin dependen*, or analgesic opioids, and stepped care, integrated services, multidisciplinary treatment, or reinforcement-based treatment. Evidenced-based data exists on the feasibility, implementation, and efficacy of stepped care models in primary care settings for the management of CP and opioid use. Although these studies did not enroll participants with OUD, they included a sub-set of patients at risk for the development of OUD. There remains a dearth of treatment options for those with comorbid CP and OUD. Future research is needed to explore the aetiology and impact of CP and OUD, and greater emphasis is needed to improve access to comprehensive pain and substance use programmes for high-risk individuals.     

The effects of heroin administration and drug cues on impulsivity

Drug addiction is a chronic relapsing disorder characterized by compulsive drug seeking and continued use despite negative consequences. Behavioral impulsivity is a strong predictor of the initiation and maintenance of drug addiction. Preclinical data suggest that heroin may exacerbate impulsive characteristics in an individual but this has yet to be assessed in clinical samples. The current secondary data analysis sought to investigate the effects of heroin on impulsivity along with the effects of exposure to drug cues. Using the current data set, we also tentatively assessed the etiological relationship between impulsivity and heroin abuse. Sixteen heroin-dependent participants were recruited to complete Immediate Memory Task/Delayed Memory Task (IMT/DMT) and GoStop tasks following repeated heroin administration, following acute heroin administration, and following a drug cue exposure session. Four preceding days of active heroin availability, compared to four preceding days of placebo drug availability, increased impulsivity assessed using the IMT and DMT. Presentation of drug cues similarly acted to increase impulsivity assessments on all three tasks. It also appears that heavier users were more susceptible to the influence of drug cues on impulsivity. The present study represents a step toward a more comprehensive understanding of the interaction between opioid abuse and impulsivity. A better understanding of these factors could provide critical insight into the maintenance of heroin use and relapse.     

Is the bipolar spectrum the psychopathological substrate of suicidality in heroin addicts?

BACKGROUND: To describe the prevalence and the risk factors of suicidal ideation in a cohort of Italian opioid addicts presenting for treatment. METHOD: Systematic cross-sectional clinical data on suicidal ideation, socio-demographic variables, psychiatric status, social adjustment, status and history of addiction in 616 patients were gathered. RESULTS: Suicidal thoughts during the past week were reported by 29.1%. Suicidal thoughts were more frequent in patients with bipolar spectrum diagnoses (OR = 1.42) and in patients with depressive and aggressive symptoms (multiple R = 0.47). The odds of having suicidal thoughts were also higher for subjects receiving public welfare benefits (OR = 1.69), unemployed patients (OR = 1.37), those with early onset of heroin dependence (OR = 1.36), living alone (OR = 1.33), and experiencing problems in organizing social contacts and leisure time (OR = 1.28). CONCLUSION: Current suicidal ideation was a common feature of patients with opioid addiction. Depression and hostility as part of the bipolar spectrum - in the context of early-onset drug dependence, work and social/leisure problems - appear independently associated with suicidal ideation. Given the elevated rates of completed suicide in heroin addiction, these data have implications for preventing suicide in patients with this type of addiction. Prospective data are needed to further address this important clinical and public health agenda.     

Mouse strain differences in locomotor,sensitisation and rewarding effect of heroin; association with alterations in MOP‐r activation and dopamine transporter binding

There is growing agreement that genetic factors play an important role in the risk to develop heroin addiction, and comparisons of heroin addiction vulnerability in inbred strains of mice could provide useful information on the question of individual vulnerability to heroin addiction. This study examined the rewarding and locomotor‐stimulating effects of heroin in male C57BL/6J and DBA/2J mice. Heroin induced locomotion and sensitisation in C57BL/6J but not in DBA/2J mice. C57BL/6J mice developed conditioned place preference (CPP) to the highest doses of heroin, while DBA/2J showed CPP to only the lowest heroin doses, indicating a higher sensitivity of DBA/2J mice to the rewarding properties of heroin vs C57BL/6J mice. In order to investigate the neurobiological substrate underlying some of these differences, the effect of chronic ‘intermittent’ escalating dose heroin administration on the opioid, dopaminergic and stress systems was explored. Twofold higher μ‐opioid receptor (MOP‐r)‐stimulated [³⁵S]GTPγS binding was observed in the nucleus accumbens and caudate of saline‐treated C57BL/6J mice compared with DBA/2J. Heroin decreased MOP‐r density in brain regions of C57BL/6J mice, but not in DBA/2J. A higher density of dopamine transporters (DAT) was observed in nucleus accumbens shell and caudate of heroin‐treated DBA/2J mice compared with heroin‐treated C57BL/6J. There were no effects on D₁ and D₂ binding. Chronic heroin administration decreased corticosterone levels in both strains with no effect of strain. These results suggest that genetic differences in MOP‐r activation and DAT expression may be responsible for individual differences in vulnerability to heroin addiction.     

(+/-)Cyclazocine blocks the dopamine response to nicotine

(+/-)Cyclazocine, synthesized by Archer in 1962, was originally tested as a treatment for heroin addiction. (+/-)Cyclazocine is a mu opioid antagonist and kappa opioid agonist, and because of these actions, would be expected to modulate dopamine release in the nucleus accumbens as well as the reinforcing effects of drugs of abuse. In a recent study (+/-)cyclazocine was reported to decrease cocaine self-administration in rats. The aim of the present study was to determine whether (+/-)cyclazocine would alter the dopaminergic effects of nicotine that are thought to mediate its rewarding effects. Using in vivo microdialysis in awake and freely moving rats, we investigated the effect of (+/-)cyclazocine (0.5 mg/kg, i.p.) on the acute dopamine response to nicotine (0.32 mg/kg, i.v. over a 5 min period, infused 30 min later) in the nucleus accumbens. (+/-)Cyclazocine significantly attenuated the increase in extracellular dopamine levels induced by the nicotine infusion and enhanced nicotine-induced increases in dopamine metabolites. (+/-)Cyclazocine alone did not significantly affect extracellular dopamine levels. However, both the (+) and (-) enantiomers of cyclazocine did alter basal dopamine levels and these effects made it difficult to assess their individual interactions with nicotine. The results suggest that the effects of both enantiomers contribute to the effects of the racemate; (+/-)cyclazocine may decrease the rewarding effect of nicotine and may be the prototype of a potentially novel treatment for smoking.     

Gamma-vinyl GABA (GVG) blocks expression of the conditioned place preference response to heroin in rats

We examined the effect of gamma-vinyl GABA (GVG) on the expression of the conditioned place preference response to intraperitoneally (i.p.) administered heroin in rats. Heroin, but not vehicle, produced a significant conditioned place preference response. Pretreatment of animals with 300 mg/kg of GVG significantly attenuated the expression of the heroin-induced conditioned place preference response. These results are the first to suggest that systemic GVG may provide an effective alternative to methadone maintenance in the treatment of heroin addiction, since it is without abuse potential and can be used for treatment outside an institutional setting.     

Treatment of opioid-dependent adolescents and young adults with buprenorphine

Rising rates of opioid use among teenagers and young adults are a public health concern. Despite short durations of opioid use compared with those of adults, youth with opioid dependence have a host of co-occurring conditions, including polysubstance abuse, psychiatric disorders, hepatitis C infection, HIV risk, and high-risk sexual and criminal behaviors. Opioid-dependent youth typically are offered outpatient/residential treatment with brief detoxification, but one study showed that heroin users fare worse following residential treatment. Although abundant research supports the use of medication-assisted treatment for opioid-dependent adults, research is only recently emerging for youth. Buprenorphine, a partial opioid agonist, was proven safe and effective in improving abstinence from opioids in two controlled clinical trials. More research is needed to determine several clinically relevant areas: appropriate duration of agonist treatment, ways to enhance medication adherence, the value of integrated treatments for co-occurring conditions, and the role of opioid antagonists in opioid-dependent youth.     

Differences in drug consumption,comorbidity and health service use of opioid addicts across six European urban regions (TREAT-project)

ObjectivesThis comparative study investigated consumption patterns, comorbidity and treatment utilization of opioid addicts in six European cities (Athens, Essen, London, Padua, Stockholm, Zurich).Subjects and methodsData were collected by structured face-to-face interviews. The representative sample comprises 599 addicts (100 patients per centre, 99 in London) at the start of a treatment episode.ResultsPatients were dependent on opioids for about 10 years. Regional differences were significant regarding the patients’ drug consumption pattern and their method of heroin administration (up to a fourth of the patients in Essen, London and Zurich usually smoke heroin). Concomitant use of benzodiazepines, cannabis and alcohol was common in all regions with the German and English samples showing the highest level of polydrug use. The prevalence of major depression was high in all regions (50%). Stockholm and London patients worry most about their physical health. Differences in the amount of needle sharing and especially in the use of public health service were prominent between the sites. Opioid addiction was a long-term disorder associated with a high burden of comorbidity and social problems in all cities.ConclusionThe results of the study show significant interregional differences of opioid addicts which might require different treatment strategies in European countries to handle the problem.     

The proenkephalin gene (PENK) and opioid dependence.

We tested the hypothesis that the alleles at the (CA)n repeat of the proenkephalin gene (PENK) might be associated with opioid addiction in 31 non-Hispanic Caucasian subjects with opioid dependence (heroin), 89 ethnically matched subjects with substance dependence other than opioid dependence and 132 controls. Among the subjects with opioid dependence, 66% carried the > or = 81 bp allele compared with 40% of subjects with other types of substance abuse (chi2 = 11.31, p < 0.004) and 49% of controls (chi2 = 6.0, p < 0.015). These results are consistent with a role of the PENK gene in opioid dependence.     

Advances in genetic studies of substance abuse in China

Summary:The importance of genetic factors in substance addiction has long been established. The rationale for this work is that understanding of the function of addiction genes and delineation of the k...     

An integration of three approaches to addiction and methadone maintenance treatment: the self-medication hypothesis,the disease model and social criticism

The two models which have most affected theory and practice of addiction medicine have been the disease model and the self-medication hypothesis. The disease model's fundamental concept is that the addicted individual is sick and suffers from a disease. The self-medication hypothesis proposes that drug and alcohol users are attempting to cope with an underlying psychological or social disorder by means of self-medication. These two viewpoints are presented in the light of a number of specific methadone maintenance treatment and drug abuse related issues such as the question whether drug abuse is an illness of the body, the mind or society; whether the disease model really de-stigmatized drug abuse; what the correct methadone dosing policy should be; the place of psychotherapy in methadone maintenance treatment and drug abuse and how polydrug abuse should be treated. These issues are discussed and an integrated approach is suggested stressing the need for social criticism and a renewed social policy towards drug abuse in general and its treatment in particular.     

Reduced grey matter in the posterior insula as a structural vulnerability or diathesis to addiction

A number of neuroimaging studies have shown that drug addiction is associated with morphological differences in several brain areas, including orbito-frontal and limbic structures. Most of these studies have investigated patients with addiction to cocaine. The neurobiological mechanisms which play a role in drug addiction are not fully understood, however, and the causal factors remain under investigation. The present study investigated morphological differences between patients with history of cocaine (N=14) and heroin (N=24) abuse and healthy matched controls (N=24). A 3D T1W MRI scan was acquired for all participants and the grey matter images of each patient group compared with those of controls. A direct comparison of the two addiction groups was also carried out. When compared with controls cocaine dependent patients had lower grey matter values in the left middle occipital gyrus, right putamen and insula, whereas heroin abusers had lower grey matter values in the right insula. The direct comparison between the two addiction groups showed that cocaine abusers had less grey matter in the right posterior cingulate, medio-temporal and cerebellar regions, whereas heroin abusers showed less grey matter in parietal regions on both sides, including postcentral gyrus and inferior parietal lobule. Reduced right posterior insular cortex was commonly found in both cocaine and heroin dependent patients. This morphological difference might represent a structural marker of addiction, which is independent of the discrete regional effects of each psychotropic substance of abuse, and might constitute a possible neurobiological vulnerability or diathesis to addiction. Equally, the discrete structural differences emerging from the direct comparison of cocaine and heroin abusers might reflect the effects of differential drug binding in the brain and/or express a form of neurobiological vulnerability which might explain individual drug choice.     

Developing a vaccine against multiple psychoactive targets: a case study of heroin

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin's effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.     

Prégabaline et risque d’addiction : une nouvelle demande de soin ?

PurposePregabalin (PRG) is a gamma-aminobutyric acid (GABA) analogue used for treatment of epilepsy, neuropathic pain, generalised anxiety disorder and currently being studied for other indications. Supported by the results of case studies and a limited number of studies, there is an ongoing debate about the addictive potential of PRG. However, evidence is scarce and no definitive assessment on the potential for abuse and dependence to PRG is available. The objective of our study was to identify the number of cases of abuse or dependence to PRG published and to study potential risk factors of addiction to PRG.MethodsWe have identified on PubMed and ScienceDirect published case studies of PRG abuse or dependence and analysed these cases on the basis of several clinical parameters.ResultsA total of 118 cases of PRG abuse or dependence were identified, including 21 isolated cases (mean age 33 years, 67 % men). The mean daily dose of PRG was 2,9 g. Current or past polydrug abuse was present in the majority of cases. Psychiatric diagnoses, other than substance-related disorders, were reported in as many patients, and almost all patients experienced withdrawal symptoms when PRG was discontinued.ConclusionCurrent literature suggests an important and growing concern for the abuse of PRG. Male sex, psychiatric and/or addiction history, including opioid addiction, may be potential risk factors for the development of addictive behaviours associated with PRG.