Appendix 1. Meeting for NIHR Programme Grant agenda on pain in children

Appendix 2. 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. We 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 2013b; 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 3. MEDLINE search strategy (via Ovid)

1. exp Child/

2. exp Adolescent/

3. exp Infant/

4. (child* or boy* or girl* or adolescen* or teen* or toddler* or preschooler* or pre‐schooler* or baby or babies or infant*)..tw

5. 1 or 2 or 3 or 4

6. exp Anticonvulsants/

7. (carbamazepine or clobazam or clonazepam or ethosuximide or gabapentin or lacosamide or lamotrigine or levetiracetam or oxcarbazepine or phenytoin or pregabalin or rufinamide or topiramate or valproate or vigabatrin or zonisamide).mp.

8. 6 or 7

9. exp Pain/

10. pain*.tw

11. 9 or 10

12. 5 and 8 and 11

13. randomized controlled trial.pt.

14. controlled clinical trial.pt.

15. randomized.ab.

16. placebo.ab.

17. drug therapy.fs.

18. randomly.ab.

19. trial.ab.

20. groups.ab.

21. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20

22. exp animals/ not humans.sh.

23. 21 nor 22

24. 12 and 23

Appendix 4. Embase search strategy (via Ovid)

1. exp Child/

2. exp Adolescent/

3. exp Infant/

4. (child* or boy* or girl* or adolescen* or teen* or toddler* or preschooler* or pre‐schooler* or baby or babies or infant*).tw.

5. 1 or 2 or 3 or 4

6. exp anticonvulsive agent/

7. (carbamazepine or clobazam or clonazepam or ethosuximide or gabapentin or lacosamide or lamotrigine or levetiracetam or oxcarbazepine or phenytoin or pregabalin or rufinamide or topiramate or valproate or vigabatrin or zonisamide).mp.

8. 6 or 7

9. exp Pain/

10. pain*.tw

11. 5 and 8 and 10

12. random$.tw.

13. factorial$.tw.

14. crossover$.tw.

15. cross over$.tw.

16. cross‐over$.tw.

17. placebo$.tw.

18. (doubl$ adj blind$).tw.

19. (singl$ adj blind$).tw.

20. assign$.tw.

21. allocat$.tw.

22. volunteer$.tw.

23. Crossover Procedure/

24. double‐blind procedure.tw.

25. Randomized Controlled Trial/

26. Single Blind Procedure/

27. or/12‐26

28. (animal/ or nonhuman/) not human/

29. 27 not 28

30. 11 and 29

Appendix 5. CENTRAL search strategy (via Cochrane Register of Studies Online)

1. MESH DESCRIPTOR Child EXPLODE ALL TREES

2. MESH DESCRIPTOR Adolescent EXPLODE ALL TREES

3. MESH DESCRIPTOR Infant EXPLODE ALL TREES

4. (child* or boy* or girl* or adolescen* or teen* or toddler* or preschooler* or pre‐schooler* or baby or babies or infant*):TI,AB,KY

5. #1 OR #2 OR #3 or #4

6. MESH DESCRIPTOR Anticonvulsants EXPLODE ALL TREES

7. (carbamazepine or clobazam or clonazepam or ethosuximide or gabapentin or lacosamide or lamotrigine or levetiracetam or oxcarbazepine or phenytoin or pregabalin or rufinamide or topiramate or valproate or vigabatrin or zonisamide):TI,AB,KY

8. #6 OR #7

9. MESH DESCRIPTOR Pain EXPLODE ALL TREES

10. pain*:TI,AB,KY

11. #9 OR #10

12. #5 AND #8 AND #11

Appendix 6. Summary of efficacy in individual studies

Appendix 7. Summary of adverse events and withdrawals in individual studies

Appendix 8. GRADE guidelines

Some advantages of utilising the GRADE process are (Guyatt 2008):

• transparent process of moving from evidence to recommendations;

• clear separation between quality of evidence and strength of recommendations;

• explicit, comprehensive criteria for downgrading and upgrading quality of evidence ratings; and

• clear, pragmatic interpretation of strong versus weak recommendations for clinicians, patients, and policymakers.

The GRADE system uses the following criteria for assigning grades of evidence:

• high: we are very confident that the true effect lies close to that of the estimate of the effect;

• moderate: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different;

• low: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect; and

• very low: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

We will decrease the grade if there is:

• serious (‐1) or very serious (‐2) limitation to study quality;

• important inconsistency (‐1);

• some (‐1) or major (‐2) uncertainty about directness;

• imprecise or sparse data (‐1); or

• high probability of reporting bias (‐1).

We will increase the grade if there is:

• strong evidence of association ‐ significant risk ratio of > 2 (< 0.5) based on consistent evidence from two or more observational studies, with no plausible confounders (+1);

• very strong evidence of association ‐ significant risk ratio of > 5 (< 0.2) based on direct evidence with no major threats to validity (+2);

• evidence of a dose response gradient (+1); or

• all plausible confounders would have reduced the effect (+1).

"In addition, there may be circumstances where the overall rating for a particular outcome would need to be adjusted per GRADE guidelines (Guyatt 2013a). For example, if there were so few data that the results were highly susceptible to the random play of chance, or if studies used LOCF imputation in circumstances where there were substantial differences in adverse event withdrawals, one would have no confidence in the result, and would need to downgrade the quality of the evidence by three levels, to very low quality. In circumstances where no data were reported for an outcome, we planned to report the level of evidence as 'no evidence to support or refute' (Guyatt 2013b)."