Relieving acute pain (RAP) study: a proof-of-concept protocol for a randomised, double-blind, placebo-controlled trial

Luana Colloca, Se Eun Lee, Meghan Nichole Luhowy, Nathaniel Haycock, Chika Okusogu, Soojin Yim, Nandini Raghuraman, Robert Goodfellow, Robert Scott Murray, Patricia Casper, Myounghee Lee, Thomas Scalea, Yvette Fouche, Sarah Murthi, Luana Colloca, Se Eun Lee, Meghan Nichole Luhowy, Nathaniel Haycock, Chika Okusogu, Soojin Yim, Nandini Raghuraman, Robert Goodfellow, Robert Scott Murray, Patricia Casper, Myounghee Lee, Thomas Scalea, Yvette Fouche, Sarah Murthi

Abstract

Introduction: Physicians and other prescribing clinicians use opioids as the primary method of pain management after traumatic injury, despite growing recognition of the major risks associated with usage for chronic pain. Placebos given after repeated administration of active treatments can acquire medication-like effects based on learning mechanisms. This study hypothesises that dose-extending placebos can be an effective treatment in relieving clinical acute pain in trauma patients who take opioids.

Methods and analysis: The relieving acute pain is a proof-of-concept randomised, placebo-controlled, double-blinded, single-site study enrolling 159 participants aged from 18 to 65 years with one or more traumatic injuries treated with opioids. Participants will be randomly assigned to three different arms. Arm 1 will receive the full dose of opioids with non-steroidal anti-inflammatory drugs (NSAIDs). Arm 2 will receive the 50% overall reduction in opioid dosage, dose-extending placebos and NSAIDs. Arm 3 (control) will receive NSAIDs and placebos. The trial length will be 3 days of hospitalisation (phase I) and 2-week, 1-month, 3-month and 6-month follow-ups (exploratory phase II). Primary and secondary outcomes include feasibility and acceptability of the study. Pain intensity, functional pain, emotional distress, rates of rescue therapy requests and patient-initiated medication denials will be collected.

Ethics and dissemination: All activities associated with this protocol are conducted in full compliance with the Institutional Review Board policies and federal regulations. Publishing this study protocol will enable researchers and funding bodies to stay up to date in their fields by providing exposure to research activity that may not otherwise be widely publicised.

Date and protocol version identifier: 3/6/2019 (HP-00078742).

Trial registration number: NCT03426137.

Keywords: dose-extending placebo; emotional distress; functional pain; opioid; pain interference; pharmacological conditioning.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Hypothesised effect of various treatments on improvement in pain management for FD, PR and C treatment groups. FD, full dose group; PR, partial reduction group; C, control group. We hypothesise that all three groups’ outcomes will improve, but that the three study drugs will contribute to this improvement to different extents.
Figure 2
Figure 2
Study schema.

References

    1. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain 2012;13:715–24. 10.1016/j.jpain.2012.03.009
    1. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. J Pain 2015;16:769–80. 10.1016/j.jpain.2015.05.002
    1. Sehgal N, Colson J, Smith HS. Chronic pain treatment with opioid analgesics: benefits versus harms of long-term therapy. Expert Rev Neurother 2013;13:1201–20. 10.1586/14737175.2013.846517
    1. Sullivan MD, Howe CQ. Opioid therapy for chronic pain in the United States: promises and perils. Pain 2013;154 Suppl 1:S94–100. 10.1016/j.pain.2013.09.009
    1. Zerzan JT, Morden NE, Soumerai S, et al. . Trends and geographic variation of opiate medication use in state Medicaid fee-for-service programs, 1996 to 2002. Med Care 2006;44:1005–10. 10.1097/01.mlr.0000228025.04535.25
    1. Kroenke K, Krebs EE, Bair MJ. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry 2009;31:206–19. 10.1016/j.genhosppsych.2008.12.006
    1. Florence CS, Zhou C, Luo F, et al. . The economic burden of prescription opioid overdose, abuse, and dependence in the United States, 2013. Med Care 2016;54:901–6. 10.1097/MLR.0000000000000625
    1. Chou R. Long-Acting opioids for chronic noncancer pain were linked to mortality. Ann Intern Med 2016;165:JC34 10.7326/ACPJC-2016-165-6-034
    1. Chou R, Turner JA, Devine EB, et al. . The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a national Institutes of health pathways to prevention workshop. Ann Intern Med 2015;162:276–86. 10.7326/M14-2559
    1. Volkow ND, McLellan AT. Opioid Abuse in Chronic Pain--Misconceptions and Mitigation Strategies. N Engl J Med 2016;374:1253–63. 10.1056/NEJMra1507771
    1. Kaplovitch E, Gomes T, Camacho X, et al. . Sex differences in dose escalation and overdose death during chronic opioid therapy: a population-based cohort study. PLoS One 2015;10:e0134550 10.1371/journal.pone.0134550
    1. Colloca L, Enck P, DeGrazia D. Relieving pain using dose-extending placebos: a scoping review. Pain 2016;157:1590–8. 10.1097/j.pain.0000000000000566
    1. Colloca L, Miller FG. Harnessing the placebo effect: the need for translational research. Philos Trans R Soc Lond B Biol Sci 2011;366:1922–30. 10.1098/rstb.2010.0399
    1. Colloca L. The placebo effect in pain therapies. Annu Rev Pharmacol Toxicol 2019;59:191–211. 10.1146/annurev-pharmtox-010818-021542
    1. Klinger R, Colloca L, Bingel U, et al. . Placebo analgesia: clinical applications. Pain 2014;155:1055–8. 10.1016/j.pain.2013.12.007
    1. Colloca L, Benedetti F. How prior experience shapes placebo analgesia. Pain 2006;124:126–33. 10.1016/j.pain.2006.04.005
    1. Klinger R, Soost S, Flor H, et al. . Classical conditioning and expectancy in placebo hypoalgesia: a randomized controlled study in patients with atopic dermatitis and persons with healthy skin. Pain 2007;128:31–9. 10.1016/j.pain.2006.08.025
    1. Fiorio M, Recchia S, Corrà F, et al. . Behavioral and neurophysiological investigation of the influence of verbal suggestion on tactile perception. Neuroscience 2014;258:332–9. 10.1016/j.neuroscience.2013.11.033
    1. Fiorio M, Recchia S, Corrà F, et al. . Enhancing non-noxious perception: behavioural and neurophysiological correlates of a placebo-like manipulation. Neuroscience 2012;217:96–104. 10.1016/j.neuroscience.2012.04.066
    1. Colloca L, Howick J. Placebos without deception: outcomes, mechanisms, and ethics. Int Rev Neurobiol 2018;138:219–40. 10.1016/bs.irn.2018.01.005
    1. Brown R, Deyo B, Riley C, et al. . Screening in trauma for opioid misuse prevention (STOMP): study protocol for the development of an opioid risk screening tool for victims of injury. Addict Sci Clin Pract 2017;12 10.1186/s13722-017-0097-6
    1. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary validation of the opioid risk tool. Pain Med 2005;6:432–42. 10.1111/j.1526-4637.2005.00072.x
    1. Krebs EE, Lorenz KA, Bair MJ, et al. . Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med 2009;24:733–8. 10.1007/s11606-009-0981-1
    1. Treede R-D, Rief W, Barke A, et al. . Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the International classification of diseases (ICD-11). Pain 2019;160:19–27. 10.1097/j.pain.0000000000001384
    1. Cooper SA, Desjardins PJ, Turk DC, et al. . Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations. Pain 2016;157:288–301. 10.1097/j.pain.0000000000000375
    1. Asmundson GJG, Bovell CV, Carleton RN, et al. . The fear of pain Questionnaire-Short form (FPQ-SF): factorial validity and psychometric properties. Pain 2008;134:51–8. 10.1016/j.pain.2007.03.033
    1. Darnall BD, Sturgeon JA, Cook KF, et al. . Development and validation of a daily pain Catastrophizing scale. J Pain 2017;18:1139–49. 10.1016/j.jpain.2017.05.003
    1. Freynhagen R, Baron R, Gockel U, et al. . painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin 2006;22:1911–20. 10.1185/030079906X132488
    1. Gloth FM, Scheve AA, Stober CV, et al. . The functional pain scale: reliability, validity, and responsiveness in an elderly population. J Am Med Dir Assoc 2001;2:110–4. 3rd 10.1016/S1525-8610(04)70176-0
    1. Cella D, Riley W, Stone A, et al. . The patient-reported outcomes measurement information system (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol 2010;63:1179–94. 10.1016/j.jclinepi.2010.04.011
    1. Ringham BM, Kreidler SM, Muller KE, et al. . Multivariate test power approximations for balanced linear mixed models in studies with missing data. Stat Med 2016;35:2921–37. 10.1002/sim.6811
    1. Berna C, Kulich RJ, Rathmell JP. Tapering long-term opioid therapy in chronic noncancer pain: evidence and recommendations for everyday practice. Mayo Clin Proc 2015;90:828–42. 10.1016/j.mayocp.2015.04.003
    1. Frank JW, Levy C, Matlock DD, et al. . Patients' perspectives on tapering of chronic opioid therapy: a qualitative study. Pain Med 2016;17:1838–47. 10.1093/pm/pnw078
    1. McAuliffe WE. Prescribing opioids for chronic pain. JAMA 2016;316 10.1001/jama.2016.9239
    1. Wen LS, Lloyd MC. Prescribing opioids for chronic pain. JAMA 2016;316 10.1001/jama.2016.9236
    1. Brummett CM, Waljee JF, Goesling J, et al. . New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg 2017;152:e170504 10.1001/jamasurg.2017.0504
    1. Field CA, Cochran G, Caetano R, et al. . Postdischarge nonmedical use of prescription opioids in at-risk drinkers admitted to urban level I trauma centers. J Trauma Acute Care Surg 2014;76:833–9. 10.1097/TA.0000000000000100
    1. Benedetti F, Colloca L, Torre E, et al. . Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 2004;7:587–8. 10.1038/nn1250
    1. Benedetti F, Pollo A, Lopiano L, et al. . Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses. J Neurosci 2003;23:4315–23. 10.1523/JNEUROSCI.23-10-04315.2003
    1. Ader R, Mercurio MG, Walton J, et al. . Conditioned pharmacotherapeutic effects: a preliminary study. Psychosom Med 2010;72:192–7. 10.1097/PSY.0b013e3181cbd38b
    1. Kirchhof J, Petrakova L, Brinkhoff A, et al. . Learned immunosuppressive placebo responses in renal transplant patients. Proc Natl Acad Sci U S A 2018;115:4223–7. 10.1073/pnas.1720548115

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa