Questions remain that cannot be confidently answered by the currently published randomized trials and that require appropriately designed studies of long-term opioid use for CNCP.
- Alternative routes of administration: There is a need for more information on efficacy and risk/benefits of intramuscular, subcutaneous, transdermal, rectal, and infusion routes of administration of opioids for CNCP.
- Opioids compared with non-opioid drugs: There is a need for well-designed equivalence and non-inferiority trials to assess the relative effectiveness and risk-to-benefit ratios of opioids compared with non-opioid drugs.
- Various clinical diagnoses: Most of the RCTs on opioids for CNCP have concerned musculoskeletal pain and neuropathic pain. There is limited literature on treating fibromyalgia pain and chronic headache with opioids other than tramadol, and no useful literature on opioids for chronic visceral pain.
- Long-term follow-up: CNCP is a long-term disorder, but the RCTs included in the current systematic review had fairly short follow-up periods, e.g., six weeks. Well-designed long-term studies are needed to clarify: a) the proportion of CNCP patients for whom opioids remain effective over months or years, and b) the potential over extended timeframes for developing opioid tolerance; hyperalgesia; loss of efficacy; complications such as hypogonadism, sexual dysfunction, or central sleep apnea; or probability of developing opioid misuse.
- Assessment of opioid misuse: There is a need for more well- designed trials of sufficient duration, with appropriate measures to identify prevalence and risks of opioid-related problems such as addiction.
- Populations with co-morbidities: There is a need for more trials dealing with safe and appropriate management of chronic pain where there is significant co-morbidity, e.g., pain in the elderly or psychiatric co-morbidity.
- Impact of research sponsorship: The majority of the randomized trials included in the systematic review were funded by the pharmaceutical industry. However, there was not sufficient information in these studies to determine if pharmaceutical industry funding might introduce publication bias. It is not known if there were small or unfavourable studies that were not submitted for publication.
- Genetic Factors: There is a need for trials regarding the influence of genetic factors in opioid metabolism, analgesic response, incidence of side effects and predisposition to misuse and addiction.