Impact of long-term opioid use for chronic non-cancer pain on misuse, abuse or addiction, overdose, falls and fractures

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To conduct a systematic review (with or without meta-analyses) of the scientific literature on the impact of long-term opioid therapy for CNCP, with a focus on (1) misuse, abuse or addiction, (2) overdose, and (3) falls and fractures.

Background

Chronic non-cancer pain (CNCP) is a significant public health problem with negative social and economic impacts. CNCP is highly prevalent in many countries. In the United States, about 100 million adults were affected by CNCP in 2008, and it was estimated that the national cost of pain ranged from $560 to $635 billion (Gaskin 2012). Recent population-based surveys in European countries including Spain, Portugal, Ireland, Denmark, Norway and Iceland have estimated that 25-35% of adults report chronic pain (Breivik 2013). Estimates from the Canadian Chronic Pain Study II, a population-based survey, found the prevalence of CNCP in Canada to be 25% (Boulanger 2007).

Opioids are the most potent analgesics available for the short-term treatment of CNCP such as low back pain (Furlan 2011). As a type of narcotic pain medication, they can have adverse effects if they are not used properly. Some studies have reported risks of long-term opioid use, including addiction, misuse, and overdose (Dunn 2010; Von Korff 2011). Some physicians are reluctant to prescribe opioids for CNCP, mainly due to concerns regarding adverse effects, medical complications, risks of diversion, and uncertainty about their efficacy with respect to functional outcomes and quality of life (Boulanger 2007; Morley-Forster 2003). These concerns are primarily related to the chronic, non-terminal nature of the condition which requires ongoing long-term opioid therapy.

Despite these concerns, the use of opioids in many western countries has increased dramatically in the last two decades. The top opioid analgesic consumers per capita include Sweden, France, Australia, Canada, Belgium and the USA (INCB 2006; Diener 2008). Canada’s recorded prescription opioid consumption increased by about 50% between 2000 and 2004, a rate of increase substantially greater than that of the USA during the same period (INCB 2006). Sweden, Australia, and France also recorded substantial increases during this time of 40%, 86% and 91% respectively (Diener 2008). Between 2000 and 2010, Canada's prescription opioid consumption increased by 203% (INCB 2011).

Description of the condition

The population of interest for this review is individuals aged 12 years and older who are experiencing CNCP that has persisted for 3 months or longer. CNCP includes, but is not limited to, conditions such as low back pain and other musculoskeletal pain, neuropathic pain, osteoarthritis, rheumatoid arthritis, fibromyalgia, headaches and migraines, complex regional pain syndrome, reflex sympathetic dystrophy, and causalgia. We will exclude studies focused on individuals receiving end of life or palliative care, as well as studies on neonatal cases, and pregnant women. Additionally, we will exclude studies focused solely on people with cancer, acute post-operative pain, ischemic pain due to vascular disease, pancreatitis, abdominal pain, sickle cell disease, and Crohn’s disease.

Description of the intervention

For this review, long-term use of opioids will be defined as administration of prescription opioid analgesics for three months duration or longer, for the purposes of treating CNCP. Opioids administered by oral, transdermal, transmucosal or rectal route will be included and opioids administered intramuscularly, intravenously or with pumps will be excluded. Experimental studies in human volunteers or animals will also be excluded.

How the intervention might work

A better understanding of the impact of long-term use of opioids for CNCP is needed. Opioids have been shown to be effective in treating CNCP, but this evidence is based on 62 randomized controlled trials of short duration (less than 16 weeks) (Furlan 2011). There is uncertainty about what happens beyond 16 weeks and whether these patients continue to exhibit benefits or if they develop complications. Opioids can have a wide range of complications such as sexual dysfunction, bowel obstruction, cognitive effects (on concentration, attention and short-term memory), traffic accidents, delayed return to work, depression, fatigue, cardiovascular events such as myocardial infarct, exacerbation of sleep apnea, and hyperalgesia/increased pain sensitivity. For the purpose of study feasibility, we focus on the complication outcomes of misuse, abuse or addiction, overdose, falls and fractures.

Why it is important to do this review

While there is evidence of the effectiveness of opioids for treating CNCP from previous review and other studies (Furlan 2006; Chou 2009), little is known about the long-term effects and complications associated with long-term use of opioids for this condition. This knowledge can empower physicians and patients to make informed decisions about the initiation, continuation, or termination of long-term opioids.

The Cochrane review by Noble et al (Noble 2010) on long-term opioid management for chronic non-cancer pain included 1 randomized trial and 25 case series assessing the following outcomes: pain relief, health-related quality of life, function, and adverse effects (e.g., nausea, vomiting, constipation). Most of the participants in the included studies had back pain. The authors found that many patients discontinued long-term opioid therapy due to adverse events or insufficient pain relief. However, patients who were able to continue opioids experienced clinically-significant pain relief. The results for function and quality of life were inconclusive. Many minor adverse events occurred, but serious adverse events, including iatrogenic opioid addiction were rare. The Noble 2010 review did not include large observational studies, nor did they report on outcomes such as overdose, falls and fractures.

Objectives

To conduct a systematic review (with or without meta-analyses) of the scientific literature on the impact of long-term opioid therapy for CNCP, with a focus on (1) misuse, abuse or addiction, (2) overdose, and (3) falls and fractures.

Methods

Criteria for considering studies for this review

Types of studies

We will include quantitative studies, namely randomized controlled trials, open-label trial extensions, observational studies, case studies, and case series. We will exclude letters, editorials, commentaries, conference proceedings, meeting abstracts, lectures and addresses, narrative reviews, and qualitative research.

Types of participants

Patients suffering from CNCP (persisting more than 3 months) who are over the age of 12 and not pregnant.

A list of conditions associated with CNCP is provided for review authors and includes conditions such as low back pain and other musculoskeletal pain, neuropathic pain, osteoarthritis, rheumatoid arthritis, fibromyalgia, headaches and migraines, complex regional pain syndrome, reflex sympathetic dystrophy, and causalgia.

We will exclude studies focusing exclusively on cancer, acute post-operative pain, ischemic pain due to vascular disease, pancreatitis, abdominal pain, sickle cell disease, and Crohn’s disease.

Types of interventions

Opioids must be taken daily or almost daily for a duration of three months.

We will include studies employing the modes of administration that are commonly used for the population with chronic pain: oral, transdermal, transmucosal or rectal. Studies focused on opioids administered intrathecally, intramuscularly or intravenously with pumps will not be included because they are not routine modes of administration outside specialized pain clinics. We consider that patients treated in tertiary care (e.g. specialized pain clinics) are different from patients seen in primary or secondary care.

We will include any types of comparator (studies with or without control groups).

Types of outcome measures

Misuse, abuse or addiction

Misuse: Use of an opioid in ways other than those intended by the prescribing physician (sometimes called 'problematic opioid use') (Ballantyne 2007).

Abuse: The intentional self-administration of a medication for a non-medical purpose such as altering one’s state of consciousness, e.g., 'getting high'. (APS/ACPM 2009).

Addiction: A primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving (Sundwall 2009).

Overdose

Incidence and prevalence of fatal and non-fatal opioid-related overdoses, both intentional and accidental.

Falls and fractures

Incidence and prevalence of any form of falls or fractures.

Search methods for identification of studies

Key terms will be identified by the review team and by a diverse group of stakeholders and knowledge users, including physicians, individuals affected by CNCP, and workers’ compensation representatives.

Electronic searches

The search terms will be combined to search the following databases from their inception dates: MEDLINE, EMBASE, CINAHL, PsycINFO, CENTRAL (The Cochrane Central Register of Controlled Trials, The Cochrane Library), and Business Source Premier. The searches will be conducted by an experienced librarian at the Institute for Work & Health (IWH) and the Cochrane Back Review Group (CBRG) and downloaded to the bibliographic software Reference Manager, where duplicates will be removed. The MEDLINE strategy is given in Appendix 1. The electronic searches will not have any language limitation.

Searching other resources

We will also ask the team content experts and the knowledge users to identify further sources as well as check references of recent systematic reviews for relevant articles not captured by the search.

Data collection and analysis

Selection of studies

Each article will be independently reviewed by two review authors using DistillerSR®. Articles will be reviewed first using titles and abstracts and a subset of the inclusion criteria and then again using the full articles and the full set of criteria. To reduce bias, the same two authors will not review all of the same articles. Instead, each author will be paired with other review authors on a rotating basis. Review author pairs will be required to reach consensus on all criteria. Where author pairs disagree, they will be encouraged to resolve their disagreement through discussion. In cases where agreement cannot be reached, a third review author will be consulted to ensure consensus is achieved. Team members will not review articles they have consulted on, authored, or co-authored.

Multiple pilot tests of the review criteria will be conducted to ensure review authors have similar understandings of the inclusion criteria. This will be done prior to the first level of screening titles and abstracts and again prior to the full text screening level. As an additional check of authors' understanding of the criteria, a quality check of a random subset of both included and excluded articles will be conducted by a third author. Any disagreements that arise from the quality check will be resolved through discussion with the review team.

Data extraction and management

The team will develop standardized data extraction forms based on existing forms and data extraction procedures previously developed and used at the IWH. Data extraction will be performed independently by two review authors. Again, author pairs will be rotated to reduce bias. Authors will not review articles they have consulted on, authored, or co-authored. Data to be extracted will include study characteristics, sample characteristics, characteristics of opioid use, outcome measures, and results. Differences in data extracted between authors will be identified and resolved by discussion. In cases where agreement cannot be reached, a third author will be consulted to ensure consensus is obtained.

Assessment of risk of bias in included studies

Separate 'Risk of bias' tools will be used for randomized controlled trials and for observational studies that have a control and do not have a control. Refer to Table 1 and Table 2 for the criteria for randomized controlled trials and non-randomized trials with a control. It will be assumed that non-randomized trials and observational studies without a control have a high risk of bias. The questions for the 'Risk of bias' tools come from several existing 'Risk of bias' assessment tools which have been adapted and combined to create tools relevant to this review (Downs 1998; Furlan 2009; SIGN 2011; Wells 2009) and take into consideration the Cochrane 'Risk of bias' criteria which can be found in Appendix 2 of this protocol (Higgins 2011).

Table 1. Risk of bias assessment in randomized controlled trials
QuestionResponse optionsSource of question
1. Was the method of randomization adequate?High/Low/UnclearExact wording from Furlan 2009
2. Was the treatment allocation concealed?High/Low/UnclearExact wording from Furlan 2009
3. Were the groups similar at baseline regarding the most important prognostic indicators?High/Low/UnclearExact wording from Furlan 2009
4. Was knowledge of the allocated interventions adequately prevented during the study from each of the following groups:
  • Patient

  • Care provider

  • Outcome assessor

  • unclear, Comment:

Adapted from Furlan 2009
5. Were outcomes measured using valid and reliable methods/instruments?High/Low/UnclearAdapted from Downs 1998
6. Was the timing of the outcome assessment similar in all groups?High/Low/UnclearExact wording from Furlan 2009
7. Which of the following best characterizes loss to follow up:

a) complete follow up

b) small loss (less than or equal to 30%)

c) large loss to follow up (greater than 30%)

d) No description

Adapted from Wells 2009
8. Are the numbers of dropouts similar in both groups?High/Low/UnclearAdapted from SIGN 2011
9. Are the characteristics of dropouts similar in both groups?High/Low/UnclearAdapted from Downs 1998
10. Were all randomized participants analyzed in the group to which they were allocated?High/Low/UnclearExact wording from Furlan 2009
11. Are there any other forms of bias that should be noted that are not captured above?High/Low/Unclear 
Table 2. Risk of bias assessment in non-randomized studies with a control group
QuestionResponse optionsSource of question
1. Were the subjects asked to participate in the study representative of the entire population from which they were recruited?High/Low/UnclearExact wording of Downs 1998
2. Were the patients in different intervention groups (trials and cohort studies) or were the cases and controls (case-control studies) recruited over the same period of time?High/Low/UnclearExact wording of Downs 1998
3. Was an attempt made to blind those measuring the main outcomes of the intervention?High/Low/UnclearExact wording of Downs 1998
4. Were the main outcome measures used accurate (valid and reliable)?High/Low/UnclearExact wording of Downs 1998
5. The measure of assessment of exposure is reliableHigh/Low/UnclearExact wording of SIGN 2011
6. Was the timing of the outcome assessment similar in all groups?High/Low/UnclearExact wording of Furlan 2009
7. Which of the following best characterizes loss to follow up:

a) complete follow up

b) small loss (less than or equal to 30%)

c) large loss to follow up (greater than 30%)

d) No description

Adapted from Wells 2009
8. Are the numbers of dropouts similar in both groups?High/Low/UnclearAdapted from SIGN 2011
9. Are the characteristics of dropouts similar in both groups?High/Low/UnclearAdapted from Downs 1998
10. Were main potential confounders measured using valid and reliable methods/instruments?High/Low/UnclearAdapted from Furlan 2009
11. Were baseline characteristics comparable between groups? If unbalanced, were differences appropriately controlled in the analysis?High/Low/UnclearAdapted from Downs 1998
12. Are there any other forms of bias that should be noted that are not captured above?High/Low/Unclear 

Two review authors will independently complete the appropriate 'Risk of bias' form for each included study. The review authors will be required to reach consensus and where this is not possible, a third author will be involved. Each study will be defined as being at high, low or unclear risk of bias based on how authors answer the 'Risk of bias' questions. A study having fewer than six 'low' or 'unclear' responses will be defined as being at high risk of bias.

Measures of treatment effect

We will report prevalence, cumulative incidence, mean difference, relative risk, odds ratio, attributable risk, and other associated measures of treatment effect.

Unit of analysis issues

We do not expect unit of analysis issues because we do not expect any cluster randomized trials. If any issues are identified, they will be managed in accordance with the advice in the Cochrane Handbook.

Dealing with missing data

We will attempt to contact the authors of the primary studies. We will also use data imputation or re-calculation (e.g. calculating standard deviation from standard error or confidence interval) if the data allows.

Assessment of heterogeneity

If possible, we will use the I² statistic > 50% to consider heterogeneity.

Assessment of reporting biases

If possible, when at least 10 studies are included in a meta-analysis, we will construct a funnel plot and ask three review authors to give their opinion as to whether they think there is a suggestion of reporting bias. We will report the consensus among the three authors.

Data synthesis

Our approach to evidence synthesis will be adapted from the Cochrane Collaboration methods for randomized trials and from other IWH reviews of non-randomized studies. For risks, we will capture or calculate the incidence and/or prevalence for the population included in each article. In situations of clinical homogeneity and low risk of bias, we will pool the results using weighted means and number needed to treat to harm (NNTH) using either fixed-effect or random-effects models, depending on statistical heterogeneity. In instances of significant study heterogeneity or high risk of bias, we will not pool the individual studies, but instead will present the results separately for each study. If pooling the studies is possible, we will use RevMan 5.2 software.

We will use the GRADE approach (GRADE Working Group 2004), as recommended in The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and by the updated CBRG method guidelines (Furlan 2009). Following GRADE guidelines, the final grade for quality of evidence for each sub-question will be categorized as: high, moderate, low, or very low. The evidence available to answer each sub-question will be graded on the following domains which are further discussed in Appendix 3 of this protocol: study design, risk of bias, inconsistency, indirectness, imprecision, publication bias, magnitude of the effect, dose-response gradient and influence of all plausible residual confounding.

Subgroup analysis and investigation of heterogeneity

We will determine relevant subgroups for the analysis of each of the four outcome categories a priori. Input from knowledge users and stakeholders will help guide important subgroups for the analyses.

A list of potential subgroups that will be considered for each outcome of interest can be found in Table 3.

Table 3. Proposed outcome subgroups for analysis
  1. SES: Socio-economic status

Misuse, abuse and addictionOverdoseFalls and fractures
Demographics (age, sex, SES, marital status)Demographics (age, sex, SES, marital status)Demographics (age, sex, SES, marital status)
Comorbidities (incl. mental health)Comorbidities (incl. mental health)Comorbidities (incl. mental health, osteoporosis etc.)
Cognitive impairmentCognitive impairmentCognitive impairment
Opioid characteristics (type, dose)Opioid characteristics (type, dose)Opioid characteristics (type, dose)
Geographical location (urban vs rural)Geographical location (urban vs rural)Geographical location (urban vs rural)
Other medications (psychotropics)Other medications (psychotropics)Other medications (psychotropics)
Personal and family history of addictions (tobacco, alcohol, illicit drugs, prescription drugs)--
Personal history of sexual abuse--
-Route of administration-
-Intentional vs accidental-
--Type of fracture
--Setting (nursing home, general population)

Sensitivity analysis

We will perform sensitivity analysis by excluding studies that do not have well-described 1) population 2) intervention, and 3) outcomes.

Acknowledgements

The review team acknowledges Sidrah Abid, Joe Ghorayeb and Navjot Brar for their contributions to the review.

Appendices

Appendix 1. MEDLINE search strategy

Database: Ovid MEDLINE(R)

Search Strategy:

--------------------------------------------------------------------------------

1. Chronic Disease/

2. "Wounds and Injuries"/

3. Amputation, Traumatic/

4. exp Arm Injuries/

5. Athletic Injuries/

6. Back Injuries/

7. exp Burns/

8. Contusions/

9. exp Dislocations/

10. exp Electric Injuries/

11. exp Fractures, Bone/

12. Fractures, Cartilage/

13. exp Hand Injuries/

14. exp Hip Injuries/

15. Lacerations/

16. exp Leg Injuries/

17. Multiple Trauma/

18. exp Neck Injuries/

19. Occupational Injuries/

20. exp Rupture/

21. Soft Tissue Injuries/

22. exp Spinal Cord Injuries/

23. exp Spinal Injuries/

24. exp "Sprains and Strains"/

25. exp Tendon Injuries/

26. exp Trauma, Nervous System/

27. Multiple Trauma/

28. Accidents, Occupational/

29. Accidents, Traffic/ or Accidental Falls/

30. exp Musculoskeletal Diseases/

31. exp Trauma, Nervous System/

32. or/1-31

33. Pain/ or pain.ti,ab.

34. 32 and 33

35. Pain/

36. Arthralgia/

37. (arthrit$ adj2 pain$).ti,ab.

38. Breakthrough pain/

39. Chronic pain/

40. Facial pain/

41. Headache/

42. Mastodynia/

43. Metatarsalgia/

44. exp Migraine Disorders/

45. exp Musculoskeletal diseases/

46. Musculoskeletal pain/

47. Neck pain/

48. exp Neuralgia/

49. Nociceptive pain/

50. Non-cancer pain?.ti,ab.

51. noncancer pain?.ti,ab.

52. non-malignant pain?.ti,ab.

53. nonmalignant pain?.ti,ab.

54. Pain, intractable/

55. Pain, referred/

56. persistent pain?.ti,ab.

57. refractory pain?.ti,ab.

58. Sciatica/

59. Shoulder pain/

60. dorsalgia.ti,ab.

61. exp Back pain/

62. backache.ti,ab.

63. exp Low Back Pain/

64. (lumbar adj pain).ti,ab.

65. coccyx.ti,ab.

66. coccydynia.ti,ab.

67. sciatica.ti,ab.

68. sciatic neuropathy/

69. spondylosis.ti,ab.

70. lumbago.ti,ab.

71. back disorder$.ti,ab.

72. or/35-71

73. 34 or 72

74. Analgesics, Opioid/

75. Narcotics/

76. Buprenorphine/

77. Codeine/

78. exp Fentanyl/

79. Hydrocodone/

80. Hydromorphone/

81. Levorphanol/

82. exp Meperidine/

83. Methadone/

84. Morphine/

85. (narcotic? or opiate$).ti,ab.

86. opioid$.mp.

87. Oxycodone/

88. Oxymorphone/

89. oxyneo.ti,ab.

90. Pentazocine/

91. exp Meperidine/

92. Dextropropoxyphene/

93. Tramadol/

94. Opium/

95. Butorphanol/

96. tapentadol.ti,ab.

97. or/74-96

98. (abilit$ adj3 work$).ti,ab.

99. Absenteeism/

100. exp "Activities of Daily Living"/

101. Affect/

102. Affective symptoms/

103. Walking/

104. ambulat$.ti,ab.

105. Anxiety/

106. Automobile driving/

107. (benefit? adj2 duration?).ti,ab.

108. daily activit$.ti,ab.

109. daily task?.ti,ab.

110. Depression/

111. Depressive Disorder, Major/

112. Mood Disorders/

113. disabilit$.mp.

114. disability absence?.ti,ab.

115. disability benefit?.ti,ab.

116. disability claim?.ti,ab.

117. disability duration.ti,ab.

118. exp Disability Evaluation/

119. Disabled persons/

120. Insurance, Disability/

121. disability leave.ti,ab.

122. disability management.ti,ab.

123. disability payment?.ti,ab.

124. disability pension?.ti,ab.

125. disability prevention.ti,ab.

126. domestic activit$.ti,ab.

127. domestic skill?.ti,ab.

128. domestic task?.ti,ab.

129. Efficiency/

130. exp Emotions/

131. employability.ti,ab.

132. employee performance.ti,ab.

133. Employment/

134. Frustration/

135. functional abilit$.ti,ab.

136. functional assessment?.ti,ab.

137. functional capacit$.ti,ab.

138. functional evaluation?.ti,ab.

139. functional impairment?.ti,ab.

140. functional limitation?.ti,ab.

141. functional outcome?.ti,ab.

142. functional status.ti,ab.

143. general health.ti,ab.

144. Happiness/

145. exp Health/

146. Health behavior/

147. Illness behavior/

148. Sick role/

149. (health adj3 perception?).ti,ab.

150. Health Status/

151. "health-related quality of life".ti,ab.

152. human activit$.ti,ab.

153. (job adj2 (loss or lost)).ti,ab.

154. job participation.ti,ab.

155. job performance.ti,ab.

156. job status.ti,ab.

157. labo?r force participation.ti,ab.

158. labo?r market reentry.ti,ab.

159. labo?r market reentry.ti,ab.

160. exp Leisure Activities/

161. life satisfaction.ti,ab.

162. exp Lifestyle/

163. long-term disabilit$.ti,ab.

164. longterm disabilit$.ti,ab.

165. ((loss or lost) adj2 time).ti,ab.

166. ((loss or lost) adj2 work$).ti,ab.

167. (maintenance adj2 work).ti,ab.

168. medical leave.ti,ab.

169. Mental Health/

170. mobility.ti,ab.

171. exp Occupations/

172. occupational disabilit$.ti,ab.

173. occupational function$.ti,ab.

174. occupational integration.ti,ab.

175. participat$.mp.

176. patient reported outcome?.ti,ab.

177. personal activit$.ti,ab.

178. personal care.ti,ab.

179. personal impairment.ti,ab.

180. personal limitation?.ti,ab.

181. personal management.ti,ab.

182. personal satisfaction/

183. personal task?.ti,ab.

184. exp Motor Activity/

185. Exercise/

186. Physical Fitness/

187. physical capacit$.ti,ab.

188. physical function$.ti,ab.

189. physical health.ti,ab.

190. physical well-being.ti,ab.

191. Pleasure/

192. presenteeism.ti,ab.

193. productivity.ti,ab.

194. psychological distress.ti,ab.

195. psychological well-being.ti,ab.

196. Psychomotor Performance/

197. "Quality of Life"/

198. "Recovery of Function"/

199. reemploy$.ti,ab.

200. (return$ adj2 employment).ti,ab.

201. (return$ adj3 work$).ti,ab.

202. role function$.ti,ab.

203. role participation.ti,ab.

204. RTW.ti,ab.

205. exp Self Care/

206. self-rated health.ti,ab.

207. Sexual behavior/

208. Sexual Dysfunction, Physiological/

209. short-term disabilit$.ti,ab.

210. shortterm disabilit$.ti,ab.

211. Sick Leave/

212. sick list$.ti,ab.

213. sick$ absence?.ti,ab.

214. sick$ benefit?.ti,ab.

215. exp Sleep/

216. exp "Sleep Initiation and Maintenance Disorders"/

217. exp Sleep Apnea Syndromes/

218. exp Sleep Disorders/

219. Continuous Positive Airway Pressure/

220. CPAP.ti,ab.

221. social function$.ti,ab.

222. Interpersonal relations/

223. Family relations/

224. Social behavior/

225. (stay$ adj3 work$).ti,ab.

226. Stress, Psychological/

227. "Task Performance and Analysis"/

228. Travel/

229. underactivity.ti,ab.

230. under activity.ti,ab.

231. Unemployment/

232. vitality.ti,ab.

233. well-being.ti,ab.

234. Work/

235. work ability.ti,ab.

236. work capacity.ti,ab.

237. work disabilit$.ti,ab.

238. work function$.ti,ab.

239. work impairment?.ti,ab.

240. work incapacity.ti,ab.

241. work limitation?.ti,ab.

242. work outcome?.ti,ab.

243. work participation.ti,ab.

244. work performance.ti,ab.

245. (work adj2 re-entry).ti,ab.

246. (work adj2 reentry).ti,ab.

247. work readiness.ti,ab.

248. work$ reintegration?.ti,ab.

249. work$ re-integration?.ti,ab.

250. work resumption?.ti,ab.

251. work status.ti,ab.

252. Workers' Compensation/

253. exp Suicide/

254. (ability adj2 drive).ti,ab.

255. exp Accidents/

256. sick day?.ti,ab.

257. Job Satisfaction/

258. exp Schools/

259. exp Education/

260. extracurricular activit$.ti,ab.

261. family involvement.ti,ab.

262. relationship?.ti,ab.

263. Marriage/

264. divorce/

265. exp Memory/

266. relocat$.ti,ab.

267. Panic Disorder/

268. exp Social Isolation/

269. kinesiophobia.mp.

270. immobil$.mp.

271. Catastrophization/

272. or/98-271

273. Death/

274. Asphyxia/

275. Brain death/

276. Death, Sudden/

277. Drowning/

278. excess dose?.ti,ab.

279. fatal outcome/

280. Hospital Mortality/

281. Mortality/

282. non-fatal$.ti,ab.

283. Overdose/

284. Poisoning/

285. Drug-Induced Liver Injury/

286. Drug Toxicity/

287. Mortality, Premature/

288. Death, Sudden/

289. Death, Sudden, Cardiac/

290. exp Hospitalization/

291. acute admission?.ti,ab.

292. ER visit?.ti,ab.

293. emergency visit?.ti,ab.

294. emergency room visit?.ti,ab.

295. Critical Care/

296. Emergencies/

297. Emergency Treatment/

298. Emergency Medical Services/

299. Emergency Service, Hospital/

300. exp Suicide/

301. suicide?.ti,ab.

302. central nervous system depression.mp.

303. CNS depression.mp.

304. Respiratory Insufficiency/

305. or/273-304

306. (aberrant adj3 behavio?r).ti,ab.

307. (abuse? and (drug? or opioid$ or substance?)).mp.

308. abuse liability.ti,ab.

309. (addict$ and (drug? or opioid$ or substance?)).mp.

310. Behavior, Addictive/

311. Crime/

312. Dangerous behavior/

313. (dependen$ and (drug? or opioid$ or substance? or physical)).mp.

314. diversion?.mp.

315. doctor shopping.ti,ab.

316. Drug Users/

317. Drug-Seeking Behavior/

318. "excessive use".ti,ab.

319. Habits/

320. "hazardous use?".mp.

321. "heavy use?".mp.

322. "illegal use?".mp.

323. "illicit use?".mp.

324. intoxication?.mp.

325. misuse?.mp.

326. "mis-use?".mp.

327. exp "Drug and Narcotic Control"/

328. "non-prescription use?".mp.

329. exp Opioid-Related Disorders/

330. "problem use".ti,ab.

331. "psychoactive effect?".mp.

332. exp Risk-Taking/

333. risk behavio?r?.mp.

334. exp Street Drugs/

335. exp Substance-Related Disorders/

336. exp Substance Withdrawal Syndrome/

337. withdrawal.mp.

338. chemical dependenc$.mp.

339. injectable drug?.mp.

340. "injection drug use".mp.

341. Substance Abuse, Intravenous/

342. snort$.mp.

343. crush$.mp.

344. skin pop$.mp.

345. rectal stuffing.mp.

346. vaginal stuffing.mp.

347. body stuffing.mp.

348. Substance Abuse Treatment Centers/

349. mood swing?.mp.

350. exp Cocaine/

351. Heroin/

352. social stigma/

353. (manipulat$ adj3 behavio?r).mp.

354. or/306-353

355. Accidental Falls/

356. exp Accidents/

357. Postural Balance/

358. bone demineralization.mp.

359. Bone Density/

360. bone loss.mp.

361. "bone mass".mp.

362. bone strength.mp.

363. exp "Bone and Bones"/

364. demineralized bone?.mp.

365. Accidents, Home/

366. exp Fractures, Bone/

367. "Wounds and Injuries"/

368. Amputation, Traumatic/

369. exp Arm Injuries/

370. Athletic Injuries/

371. Back Injuries/

372. exp Burns/

373. Contusions/

374. exp Dislocations/

375. exp Electric Injuries/

376. exp Fractures, Bone/

377. Fractures, Cartilage/

378. exp Hand Injuries/

379. exp Hip Injuries/

380. Lacerations/

381. exp Leg Injuries/

382. Multiple Trauma/

383. exp Neck Injuries/

384. Occupational Injuries/

385. exp Rupture/

386. Soft Tissue Injuries/

387. exp Spinal Cord Injuries/

388. Spinal Injuries/

389. exp "sprains and strains"/

390. exp Tendon Injuries/

391. exp Trauma, Nervous System/

392. exp Bone Diseases, Metabolic/

393. exp Osteoporosis/

394. postural instability.mp.

395. postural stability.mp.

396. slip$.mp.

397. stumbl$.mp.

398. trip$.mp.

399. tumbl$.mp.

400. ER visit?.mp.

401. emergency room visit?.mp.

402. emergency visit?.mp.

403. Critical Care/

404. Emergencies/

405. Emergency Treatment/

406. Emergency Medical Services/

407. Emergency Service, Hospital/

408. exp Hospitalization/

409. hospital admission?.mp.

410. immobili$.mp.

411. or/355-410

412. or/98-411

413. 73 and 97 and 412

414. animals/ not humans/

415. 413 not 414

Appendix 2. Risk of bias criteria

Random sequence generation (selection bias)

Selection bias (biased allocation to interventions) due to inadequate generation of a randomized sequence

There is a low risk of selection bias if the investigators describe a random component in the sequence generation process such as: referring to a random number table, using a computer random number generator, coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots, minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).

There is a high risk of selection bias if the investigators describe a non-random component in the sequence generation process, such as: sequence generated by odd or even date of birth, date (or day) of admission, hospital or clinic record number; or allocation by judgement of the clinician, preference of the participant, results of a laboratory test or a series of tests, or availability of the intervention.

Allocation concealment (selection bias)

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

There is a low risk of selection bias if the participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; or sequentially-numbered, opaque, sealed envelopes.

There is a high risk of bias if participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; or other explicitly unconcealed procedures.

Blinding of participants

Performance bias due to knowledge of the allocated interventions by participants during the study

There is a low risk of performance bias if blinding of participants was ensured and it was unlikely that the blinding could have been broken; or if there was no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding.

Blinding of personnel/ care providers (performance bias)

Performance bias due to knowledge of the allocated interventions by personnel/care providers during the study

There is a low risk of performance bias if blinding of personnel was ensured and it was unlikely that the blinding could have been broken; or if there was no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding.

Blinding of outcome assessor (detection bias)

Detection bias due to knowledge of the allocated interventions by outcome assessors

There is low risk of detection bias if the blinding of the outcome assessment was ensured and it was unlikely that the blinding could have been broken; or if there was no blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding, or:

  • for patient-reported outcomes in which the patient was the outcome assessor (e.g. pain, disability): there is a low risk of bias for outcome assessors if there is a low risk of bias for participant blinding (Boutron 2005)

  • for outcome criteria that are clinical or therapeutic events that will be determined by the interaction between patients and care providers (e.g. co-interventions, length of hospitalisation, treatment failure), in which the care provider is the outcome assessor: there is a low risk of bias for outcome assessors if there is a low risk of bias for care providers (Boutron 2005)

  • for outcome criteria that are assessed from data from medical forms: there is a low risk of bias if the treatment or adverse effects of the treatment could not be noticed in the extracted data (Boutron 2005)

Incomplete outcome data (attrition bias)

Attrition bias due to amount, nature or handling of incomplete outcome data

There is a low risk of attrition bias if: there were no missing outcome data; reasons for missing outcome data were unlikely to be related to the true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data were balanced in numbers, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with the observed event risk was not enough to have a clinically-relevant impact on the intervention effect estimate; for continuous outcome data, the plausible effect size (difference in means or standardized difference in means) among missing outcomes was not enough to have a clinically-relevant impact on observed effect size, or missing data were imputed using appropriate methods (if drop-outs are very large, imputation using even 'acceptable' methods may still suggest a high risk of bias) (van Tulder 2003). The percentage of withdrawals and drop-outs should not exceed 20% for short-term follow-up and 30% for long-term follow-up and should not lead to substantial bias (these percentages are commonly used but arbitrary, not supported by literature) (van Tulder 2003).

Selective reporting (reporting bias)

Reporting bias due to selective outcome reporting

There is a low risk of reporting bias if the study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way, or if the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

There is a high risk of reporting bias if not all of the study's pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Group similarity at baseline (selection bias)

Bias due to dissimilarity at baseline for the most important prognostic indicators.

There is low risk of bias if groups are similar at baseline for demographic factors, value of main outcome measure(s), and important prognostic factors (examples in the field of back and neck pain are duration and severity of complaints, vocational status, percentage of patients with neurological symptoms) (van Tulder 2003).

Co-interventions (performance bias)

Bias because co-interventions were different across groups

There is low risk of bias if there were no co-interventions or they were similar between the index and control groups (van Tulder 2003).

Compliance (performance bias)

Bias due to inappropriate compliance with interventions across groups

There is low risk of bias if compliance with the interventions was acceptable, based on the reported intensity/dosage, duration, number and frequency for both the index and control intervention(s). For single-session interventions (e.g. surgery), this item is irrelevant (van Tulder 2003).

Intention-to-treat-analysis

There is low risk of bias if all randomized patients were reported/analyzed in the group to which they were allocated by randomization.

Timing of outcome assessments (detection bias)

Bias because important outcomes were not measured at the same time across groups

There is low risk of bias if all important outcome assessments for all intervention groups were measured at the same time (van Tulder 2003).

Other bias

Bias due to problems not covered elsewhere in the table

There is a low risk of bias if the study appears to be free of other sources of bias not addressed elsewhere (e.g. study funding).

Appendix 3. The GRADE approach to evidence synthesis

The quality of evidence will be categorized as follows:

  • High (⊙⊙⊙⊙): further research is very unlikely to change the confidence in the estimate of effect.

  • Moderate (⊙⊙⊙○): further research is likely to have an important impact in the confidence in the estimate of effect.

  • Low (⊙⊙○○): further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

  • Very Low (⊙○○○): any estimate of effect is very uncertain.

The evidence available to answer each sub-question will be graded on the domains in the following manner:

1. Study design

2. Risk of bias

Limitations in the study design and implementation may bias the estimates of the treatment effect. Our confidence in the estimate of the effect and in the following recommendation decreases if studies suffer from major limitations. we will examine all studies on five types of biases:

a) Selection (random sequence generation, allocation concealment, group similarities at baseline)

b) Performance (blinding of participants, blinding of healthcare providers)

c) Attrition (drop outs and intention-to-treat analysis)

d) Measurement (blinding of the outcome assessors and timing of outcome assessment)

e) Reporting bias (selective reporting)

3. Inconsistency

Inconsistency refers to an unexplained heterogeneity of results. Widely differing estimates of the treatment effect (i.e. heterogeneity or variability in results) across studies suggest true differences in underlying treatment effect. Inconsistency may arise from differences in: populations (e.g. drugs may have larger relative effects in sicker populations), interventions (e.g. larger effects with higher drug doses), or outcomes (e.g. diminishing treatment effect with time). The quality of evidence will be downgraded as follows:

  • by one level: when the heterogeneity or variability in results is large (for example: I2 above 80%)

  • by two levels: when the heterogeneity or variability in results is large AND there was inconsistency arising from populations, interventions or outcomes.

4. Indirectness

Indirect population, intervention, comparator, or outcome – the question being addressed in this systematic review is different from the available evidence regarding the population, intervention, comparator, or an outcome in the included randomized trial.

The quality of evidence will be downgraded as follows:

  • by one level: when there is indirectness in only one area

  • by two levels: when there is indirectness in two or more areas

5. Imprecision

Results are imprecise when studies include relatively few patients and few events and thus have wide confidence intervals around the estimate of the effect. In this case we judge the quality of the evidence lower than it otherwise would because of resulting uncertainty in the results. Each outcome is considered separately.

For dichotomous outcomes

We will consider imprecision for either of the following two reasons:

  1. There is only one study. When there is more than one study, the total number of events is less than 300 (a threshold rule-of-thumb value) (Mueller 2007).

  2. 95% confidence interval around the pooled or best estimate of effect includes both 1) no effect and 2) appreciable benefit or appreciable harm. The threshold for 'appreciable benefit' or 'appreciable harm' is a relative risk reduction (RRR) or relative risk increase (RRI) greater than 25%.

The quality of the evidence will be downgraded as follows:

  • by one level: when there is imprecision due to (1) or (2)

  • by two levels: when there is imprecision due to (1) and (2)

For continuous outcomes

We will consider imprecision for either of the following two reasons:

  1. There is only one study. When there is more than one study, total population size is less than 400 (a threshold rule-of-thumb value; using the usual α and β, and an effect size of 0.2 SD, representing a small effect)

  2. 95% confidence interval includes no effect and the upper or lower confidence limit crosses an effect size (standardized mean difference) of 0.5 in either direction.

The quality of the evidence will be downgraded as follows:

  • by one level: when there is imprecision due to (1) or (2)

  • by two levels: when there is imprecision due to (1) and (2)

6. Publication bias

Publication bias is a systematic underestimate or an overestimate of the underlying beneficial or harmful effect due to the selective publication of studies. The quality of evidence will be downgraded as follows:

  • by one level: when the funnel plot suggests publication bias

7. Magnitude of the effect

8. Dose response gradient

9. Influence of all plausible residual confounding

Contributions of authors

Roles and responsibilities
Task Who has agreed to undertake the task?
Draft the protocolAndrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide
Develop a search strategy

Quenby Mahood, Andrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide, Claire Munhall

As well as input on search terms from knowledge users and stakeholders

Search for studiesQuenby Mahood
Obtain copies of studiesJoanna Liu
Select which studies to includeAndrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide, Claire Munhall, Melanie Fortune, Sidrah Abid, Joe Ghorayeb, Navjot Brar
Extract data from studiesAndrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide, Claire Munhall
Enter data into RevMan/ DistillerClaire Munhall
Carry out the analysisAndrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide, Claire Munhall
Interpret the analysisAndrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide, Claire Munhall
Draft the final reviewAndrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide, Claire Munhall
Update the reviewAndrea Furlan, Emma Irvin, Dwayne Van Eerd, Nancy Carnide, Claire Munhall

Declarations of interest

None known

Sources of support

Internal sources

  • Canadian Institutes for Health Research (CIHR), Canada.

    Knowledge Synthesis Grant

External sources

  • No sources of support supplied

Ancillary