Appendix 1. Methodological considerations for chronic pain

There have been several recent changes in how the efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with new criteria for what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with 'any improvement'. Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be of longer duration, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for the inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. To summarise some of the recent insights that must be considered in this new review:

1. Pain results tend to have a U‐shaped distribution rather than a bell‐shaped distribution. This is true in acute pain (Moore 2011a; Moore 2011b), back pain (Moore 2010d), and arthritis (Moore 2010c), as well as in fibromyalgia (Straube 2010); in all cases average results usually describe the experience of almost no‐one in the trial. Data expressed as averages are potentially misleading, unless they can be proven to be suitable.

2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials of less than 12 weeks duration, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2010c); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic‐type pain.

3. The proportion of patients with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis to 30% in fibromyalgia (Moore 2009; Moore 2010c; Moore 2013a; Moore 2014b; Straube 2008; Sultan 2008). A Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.

4. Individual patient analyses indicate that patients who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (Moore 2010b; Moore 2014a).

5. Imputation methods such as last observation carried forward (LOCF), used when participants withdraw from clinical trials, can overstate drug efficacy especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012).

Appendix 2. Search strategy for MEDLINE (via Ovid)

1 exp Methadone/
2 (methadon* or d‐methadone or l‐methadone or r‐methadone or s‐methadone or dolophine or phenadone or physeptone or phymet or symoron or metadol or metasedin or methaddict or methadose or methex or pinadone or amidone or biodone).tw.
3 1 or 2
4 exp Pain/
5 exp Peripheral Nervous System Diseases/
6 exp Somatosensory Disorders/
7 ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier]
8 ((neur* or nerv*) adj6 (compress* or damag*)).mp.
9 or/4‐8
10 3 and 9
11 randomized controlled trial.pt.
12 controlled clinical trial.pt.
13 randomized.ab.
14 placebo.ab.
15 drug therapy.fs.
16 randomly.ab.
17 trial.ab.
18 groups.ab.
19 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18
20 exp animals/ not humans.sh.
21 19 not 20
22 10 and 21

Appendix 3. GRADE: criteria for assigning grade of evidence

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Chapter 12, Higgins 2011).

1. High: randomised trials; or double‐upgraded observational studies.

2. Moderate: downgraded randomised trials; or upgraded observational studies.

3. Low: double‐downgraded randomised trials; or observational studies.

4. Very low: triple‐downgraded randomised trials; or downgraded observational studies; or case series/case reports.

Factors that may decrease the quality level of a body of evidence are:

1. limitations in the design and implementation of available studies suggesting high likelihood of bias;

2. indirectness of evidence (indirect population, intervention, control, outcomes);

3. unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);

4. imprecision of results (wide confidence intervals);

5. high probability of publication bias.

Factors that may increase the quality level of a body of evidence are:

1. large magnitude of effect;

2. all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect;

3. dose‐response gradient.