Description of the condition

Pain is described as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (Merskey 1994). Chronic pain is typically described as pain on most days for at least three months. Chronic non‐cancer pain (CNCP) is any chronic pain that is not due to a malignancy. Chronic non‐cancer pain is frequently divided into neuropathic pain (i.e. pain originating in nerves) and non‐neuropathic or nociceptive pain, which is often musculoskeletal in origin and arises from structures such as muscles, bones, or ligaments.

Chronic non‐cancer pain is very common in adults. A recent review estimated the prevalence of CNCP (of moderate or severe intensity, lasting more than three months) at approximately 20%, with considerable variation between studies (Moore 2014). The impact of CNCP on life is substantial, affecting quality of life and activities of daily living, social life, and work, with approximately 20% of people with chronic pain unable to work due to pain (Moore 2014).

The personal and subjective nature of pain makes objective measurement impossible; the assessment of pain is subjective and based on individual report (Breivik 2008). Different instruments are used to measure pain and to determine its impact on the physical, social, emotional, and spiritual aspects of life.

Description of the interventions

The treatment of pain may encompass a variety of approaches, including pharmacological management. Effective pain therapy has been described in terms of a reduction in pain intensity of at least 50% over study baseline, and results in consistent improvements in fatigue, sleep, depression, quality of life, and work ability (Moore 2014). Opioid therapy is used for the treatment of both acute and chronic pain conditions. There is a large number of policies and guidelines to assist with the use of opioids for the management of chronic pain. The World Health Organization (WHO) published a field‐tested analgesic ladder to guide the use of sequentially stronger pain medications for the relief of cancer pain, including opioids and non‐opioids such as non‐steroidal anti‐inflammatory drugs (NSAIDs) (WHO 1996). This tool is now applied generally for people who require analgesic treatment and is widely used for both cancer and non‐cancer pain (Vargas‐Schaffer 2010).

Long‐term opioid use may be associated with problematic patterns of use, leading to clinically significant impairment or distress, including substance use disorders (i.e. abuse and dependence). Opioid use may also be associated with somatic and psychological sequelae, including depressive disorders, anxiety disorders, sleep disorders, sexual dysfunction, and delirium (APA 2013). Furthermore, chronic opioid use is associated with a risk of fatal and non‐fatal overdose, as well as cardiovascular events, endocrinological harms, and motor vehicle accidents (Dowell 2016). High‐quality evidence demonstrates that an increased risk of vehicle crashes exists with the use of opioids (Hegmann 2014a). Operating a vehicle is considered a surrogate for safety‐sensitive work tasks, and hence the use of opioids is usually deemed incompatible with working in safety‐sensitive positions (Hegmann 2014a), and may also be incompatible with decision‐critical tasks. Opioid use may therefore have direct implications on ability to work and economic productivity.

The American College of Occupational and Environmental Medicine's Evidence‐based Practice Guidelines conclude that quality evidence (moderate or high quality) does not support the concept of superiority of opioids over NSAIDs or other medications for the treatment of CNCP (Hegmann 2014b). Estimates of efficacy may also be inflated by inappropriate imputation methods (McQuay 2012). Furthermore, there is a relative dearth of literature available on how to discontinue opioids in high‐dose users (Windmill 2013).

In view of the absence of dependable, high‐quality evidence for long‐term benefits with the use of opioids for CNCP, the Centers for Disease Control and Prevention suggest utilising the lowest effective dose, with careful reassessment of benefits versus risks when increasing the dose to 50 morphine milligram equivalents or more per day (Dowell 2016).

How the intervention might work

This overview focused on the use of opioids for their key function of analgesia. Opium is a plant‐derived substance, with pharmacologically active ingredients including morphine and codeine. The term 'opioids' can refer to either naturally occurring compounds ('opiates') or synthetic compounds. Opioids act by binding to opioid receptors; mu, kappa, and delta opioid receptors are widely distributed throughout the nervous system (Rachinger‐Adam 2011). Opioids bring about complex changes at the cellular and molecular level, decreasing pain perception and increasing tolerance to painful stimuli (Borg 2014).

Other opioid actions include euphoria (Schulteis 1996), sedation, drowsiness, and endocrine dysregulation (Vuong 2010). Opioids alter sleep regulation, and are associated with poor sleep quality, insomnia, respiratory depression, sleep apnoea, and sleep‐disordered breathing (Zutler 2011). Physiological dependence on opioids may develop rapidly after the initiation of opioid use, leading to opioid abuse and dependence (opioid use disorder). Increasing doses of opioids over time are a common and significant concern with this group of medications (Kosten 2002).

A number of effects have been identified with the acute administration of opioids or in opioid‐naive people; it has been suggested that chronic opioid use results in fewer medical problems (Rass 2014). However, there are serious and potentially lethal adverse effects that may occur with long‐term use.

Why it is important to do this overview

Opioids are now commonly and increasingly used for the treatment of pain, including CNCP (Zutler 2011). In fact, there has been a large increase in the use of opioids for CNCP in recent years despite safety concerns and a lack of convincing evidence of effectiveness (Kidner 2009; Chapman 2010; Bohnert 2012). Evidence of utilisation of larger doses of opioids for the treatment of CNCP is emerging. For example, one analysis of Workers' Compensation Board (WCB) data (where the vast majority of claimants with pain would have non‐malignant pain) from Manitoba, Canada, demonstrated a dramatic increase in the average opioid dose prescribed over time: from less than 500 morphine milligram equivalents per person per year in 1998 to over 6000 morphine milligram equivalents per person per year in 2010. Moreover, compared to other Manitobans, the WCB claimant population was about twice as likely to be prescribed doses above 120 morphine milligram equivalents per day (Kraut 2015). Opioid use often continues post‐claim, and both duration and dose of post‐claim opioid use are correlated with the dose during the claim (Shafer 2015). Dramatic increases in the number of opioid prescriptions have been seen across the world since the 2000s, for example in the UK (Zin 2014), Australia (Leong 2009), and the USA (Manchikanti 2012a). The rate of dispensing of high‐dose opioids specifically (i.e. doses of 200 morphine milligram equivalents per day or greater) increased in Canada by 23% between 2006 and 2011 (Gomes 2014).

The previous perception of the adverse event profile associated with opioid use may have contributed to the current opioid use and overdose epidemic in North America, which has been decades in the making. A letter published in The New England Journal of Medicine in 1980 examined the incidence of narcotic addiction in 39,946 hospitalised medical patients and suggested that addiction was rare in patients treated with opioids (Porter 1980). Later in the 1980s, Portenoy and Foley described an addiction risk of lower than 1% (Portenoy 1986). By current standards, most of the patients in that study were not on high‐dose opioids: two‐thirds (n = 25) required a dose of less than 20 morphine milligram equivalents per day, while only four participants received more than 40 morphine milligram equivalents per day (Portenoy 1986). Another survey of 100 participants receiving opioids for CNCP (mean treatment duration 224 days) suggested partial or good relief for almost 80% of those participants, with the most common adverse events listed as nausea and constipation, but no reported cases of respiratory depression or addiction (Zenz 1992). Guidelines for managing CNCP published in 1995 in the Canadian Family Physician cited evidence in support of an extremely low risk of addiction and evidence of high rates of efficacy of opioids for CNCP, as well as a relative paucity of adverse events in people first receiving opioids for medical reasons (Hagen 1995).

However, the liberal use of opioids for CNCP has come under scrutiny due to questions about their effectiveness and the potential for adverse events, abuse, and addiction (NOUGG 2010; Franklin 2014; Häuser 2014; Nuckols 2014; Katz 2015). There has recently been considerable criticism of earlier publications and their role in contributing to the opioid epidemic. One seminal paper, Porter 1980, was described as having been "heavily and uncritically cited as evidence that addiction was rare with long‐term opioid therapy. We believe that this citation pattern contributed to the North American opioid crisis by helping to shape a narrative that allayed prescribers’ concerns about the risk of addiction associated with long‐term opioid therapy" (Leung 2017).

The updated Canadian opioid guidelines, Busse 2017, had also come under criticism for potential financial conflicts of interest (Howlett 2017), highlighting the need for independent and unbiased summaries of the evidence such as those provided by Cochrane.

In contrast to the early and more permissive approaches to opioid use for CNCP, more recent evidence suggests that opioid abuse and addiction are well documented among people with chronic pain (Vowles 2015). There is a potential for opioid addiction to develop even if these compounds are used for the management of severe pain (Kosten 2002; Huffman 2015; Vowles 2015). The risk for addiction increases with increasing opioid doses. Huffman and colleagues reported that a 50‐milligram increase in oral morphine milligram equivalent dose almost doubled the risk of addiction; a 100‐milligram dose increase was associated with a three‐fold increase in that risk (Huffman 2015).

There is furthermore the potential for serious adverse events. Serious adverse events, as defined by the US Food and Drug Administration, are those with patient outcomes of life‐threatening effects, hospitalisation, disability or permanent damage, intervention to prevent permanent impairment, drug dependence or abuse, death, or another event that jeopardises the patient or requires treatment to prevent one of the other outcomes (FDA 2016). Some outcomes, including sleep‐disordered breathing and respiratory depression, may result in opioid‐associated deaths and demonstrate a clear relationship to dose (Walker 2007; Jungquist 2012). Drug interactions are another concern, as is interaction with alcohol, which can result in several types of serious adverse events (McCance‐Katz 2010).

Hegmann and colleagues summarised the substantial increase in the use of opioids and the increase in deaths associated with opioids (Hegmann 2014b). Opioid‐related deaths are common and can occur even when the prescription is in accordance with guidelines. Most opioid‐related deaths in the USA (60%) occurred in people given prescriptions based on prescribing guidelines by medical boards (with 20% of deaths at doses of 100 morphine milligram equivalents per day or less, and 40% in people who received doses above that threshold). The remaining 40% of deaths occurred in people abusing the drugs (Manchikanti 2012a). Abuse of opioids may be related to multiple prescriptions/'double‐doctoring', requesting early refills, and drug diversion.

A consensus is emerging that long‐term opioid therapy for CNCP may be appropriate only for well‐selected populations (Manchikanti 2012b). Furthermore, agreement is building that high‐dose opioid treatment should be used with extreme caution for indications other than cancer pain.