Context Chronic pain and opioid dependence confer substantial individual and societal burdens and are notoriously difficult to treat effectively. Their comorbid presentation further complicates effective treatment through complex physiological and environmental interactions. Objectives (1) What are the clinical characteristics and treatment outcomes associated with comorbid chronic pain in ORT patients? (2) Does the patient-attributed direction of the causal relationship in the development of opioid dependence and chronic pain identify two clinically-distinct treatment populations? (3) What is the incidence of iatrogenic opioid dependence or abuse following opioid analgesic treatment? (4) Is there evidence of opioid-induced hyperalgesia in humans? Methods Primary data Participants were 467 treatment-seeking, opioid-dependent patients. Materials comprised standardised instruments – focusing on illicit substance use and mental health characteristics – completed by medical staff at study inception, and extracts of routinely-collected clinical datasets spanning the follow-up period. Procedures involved the use of a health informatics approach. Electronic linkage of data collected at study inception with routinely-collected clinical datasets spanning the 5-year follow-up period. Secondary data Systematic searches were undertaken using six electronic research databases, supplemented by manual searches. Study quality was assessed using instruments developed by NIH. Data synthesis using random effects models (DerSimonian-Laird method) generated: (1) a pooled incidence of iatrogenic dependence or abuse following opioid analgesic treatment; and (2) a pooled effect of opioid exposure on the development of opioid-induced hyperalgesia. Additional analyses included assessment of heterogeneity in study effects, within- and between-study risk of bias and sensitivity analyses. Results A total of 246 (53%) patients reported comorbid chronic pain. This ‘comorbid’ group was associated with increased mortality, physical and mental health problems, service utilisation and illicit drug use, specifically benzodiazepines and cannabinoids. Within the ‘comorbid’ group, patients who reported a causal impact of opioid dependence on the development of pain were associated with increased illicit drug use and psychiatric morbidity. Secondary data analyses revealed a 4.7% incidence estimate of iatrogenic dependence or abuse following opioid analgesic treatment, and evidence of the development of opioid-induced hyperalgesia following therapeutic opioid exposure. Conclusions Elevated mortality, morbidity and illicit drug use in opioid-dependent patients with comorbid chronic pain reflects a patient population with substantial health burdens. The dynamic relationship between these severe and chronic conditions necessitates complex, multimodal treatment strategies and multiagency collaboration, including general psychiatric intervention. Whilst a substantial proportion reported that opioid dependence developed as a consequence of pain problems, there is evidence to suggest that the assumed risk of iatrogenic opioid dependence and abuse may be an overestimate; however, therapeutic opioids may lead to other problems that impact on treatment effectiveness, such as opioid-induced hyperalgesia.