Advertisement

Combination Drug Therapy for the Management of Low Back Pain and Sciatica: Systematic Review and Meta-Analysis

      Highlight points

      • Combining medicines may have advantages compared with single-ingredient medicines.
      • Of the 27 eligible studies, most combinations (21 of 23) were of single trials.
      • Most combinations had very low or low quality of evidence.
      • The evidence is limited for combination drug therapy for back pain or sciatica.

      Abstract

      Combining medicines may give greater pain relief and/or improved tolerability. We conducted a systematic review to investigate the effects of combination drug therapy in patients with low back pain and/or sciatica on pain, disability, and adverse events. Databases and trial registers were searched from inception to July 27, 2017, for randomized trials of (sub)acute or chronic back pain or sciatica participants that were administered combination drug therapy compared with monotherapy or placebo. Of the 27 studies included, most combinations (21 of 23) consisted of single trials. Most combinations had no or small effect on pain and disability. A clinically important difference was found in one combination, buprenorphine plus pregabalin versus buprenorphine for chronic back pain at immediate (mean difference = –23.30; 95% confidence interval = –27.68 to –18.92) and short (mean difference = –27.60; 95% confidence interval = –31.70 to –23.50) terms; however, the quality of evidence was low. There was no statistically significant increased risk of serious adverse events. When the risk of adverse events was statistically significant, it favored monotherapy or placebo. There is no clear evidence to support any combination drug therapy for the management of low back pain and sciatica due to the limited number of studies and overall low quality of evidence.
      Perspective: Combining medicines may give greater pain relief and/or improved tolerability compared with single-ingredient medicines. However, the lack of studies and overall low quality of evidence limit the recommendation of combination drug therapy for the management of low back pain and sciatica.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Attal N
        • Perrot S
        • Fermanian J
        • Bouhassira D
        The neuropathic components of chronic low back pain: a prospective multicentre study using the DN4 questionnaire.
        J Pain. 2011; 12: 1080-1087
        • Baron R
        • Martin-Mola E
        • Muller M
        • Dubois C
        • Falke D
        • Steigerwald I
        Effectiveness and s afety of tapentadol prolonged release (PR) versus a combination of tapentadol PR and pregabalin for the management of severe, chronic low back pain with a neuropathic component: a randomized, double-blind, phase 3b study.
        Pain Pract. 2015; 15: 455-470
        • Berry H
        • Hutchinson DR
        Tizanidine and ibuprofen in acute low-back pain: results of a double-blind multicentre study in general practice.
        J Int Med Res. 1988; 16: 83-91
        • Blahova Z
        • Holm JC
        • Weiser T
        • Richter E
        • Trampisch M
        • Akarachkova E
        Nicoboxil/nonivamide cream effectively and safely reduces acute nonspecific low back pain - a randomized, placebo-controlled trial.
        J Pain Res. 2016; 9: 1221-1230
        • Borenstein DG
        • Lacks S
        • Wiesel SW
        Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm.
        Clin Ther. 1990; 12: 125-131
        • Bruggemann G
        • Koehler CO
        • Koch EMW
        The therapy of acute lumbago with diclofenac and B-vitamins — results of a double-blind clinical study.
        Klin Wochenschr. 1990; 68: 116-120
        • Chaparro LE
        • Wiffen PJ
        • Moore RA
        • Gilron I
        Combination pharmacotherapy for the treatment of neuropathic pain in adults (review).
        Cochrane Database Syst Rev. 2012; 11: CD008943
        • Friedman BW
        • Irizarry E
        • Solorzano C
        • Khankel N
        • Zapata J
        • Zias E
        • Gallagher EJ
        Diazepam is no better than placebo when added to naproxen for acute low back pain.
        Ann Emerg Med. 2017; 70: 169-176
        • Freynhagen R
        • Baron R
        • Gockel U
        • Tolle TR
        PainDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain.
        Curr Med Res Opin. 2006; 22: 1911-1920
        • Furlan AD
        • Malmivaara A
        • Chou R
        • Maher CG
        • Deyo RA
        • Schoene M
        • Bronfort G
        • van Tulder MW
        • Editorial Board of the Cochrane Back, Neck Group
        2015 Updated method guidelines for systematic reviews in the Cochrane Back and Neck Group.
        Spine. 2015; 40 (1660-1641, 2015)
        • Gaskell H
        • Derry S
        • Moore RA
        • McQuay HJ
        Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults.
        Cochrane Database Syst Rev. 2009; 8CD002763
        • Gaubitz M
        • Schiffer T
        • Holm C
        • Richter E
        • Pisternick-Ruf W
        • Weiser T
        Efficacy and safety of nicoboxil/nonivamide ointment for the treatment of acute pain in the low back- a randomized, controlled trial.
        Eur J Pain. 2016; 20: 263-273
        • Gilron I
        • Bailey JM
        • Tu D
        • Holden RR
        • Jackson AC
        • Houlden RL
        Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial.
        Lancet. 2009; 374: 1252-1261
        • Gilron I
        • Jensen TS
        • Dickenson AH
        Combination pharmacotherapy for management of chronic pain: from bench to bedside.
        Lancet Neurol. 2013; 12: 1084-1095
        • Guyatt GH
        • Oxman AD
        • Vist GE
        • Falck-Ytter Y
        • Schunemann H
        GRADE: What is "quality of evidence" and why is it important to clinicians.
        BMJ. 2008; 336: 995-998
        • Hall GC
        • Morant SV
        • Carroll D
        • Gabriel ZL
        • McQuay HJ
        An observational descriptive study of the epidemiology and treatment of neuropathic pain in a UK general population.
        BMC Fam Pract. 2013; 4: 28
        • Hancock MJ
        • Maher CG
        • Latimer J
        • McLachlan AJ
        • Cooper CW
        • Day RO
        • Spindler MF
        • McAuley JH
        Assessment of diclofenac or spinal manipulative therapy, or both, in addition to recommended first-line treatment for acute low back pain: a randomised controlled trial.
        Lancet. 2007; 370: 1638-1643
        • Higgins JPT
        • Green S
        Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011].
        The Cochrane Collaboration, Copenhagen2011
        • Hoy D
        • March L
        • Brooks P
        • Blyth FM
        • Woolf A
        • Bain C
        • Williams G
        • Smith E
        • Vos T
        • Barendregt J
        • Murray C
        • Burstein R
        • Buchbinder R
        The global burden of low back pain: estimates from the Global Burden of Disease 2010 study.
        Ann Rheum Dis. 2014; 73: 968-974
        • Koes B
        • van Tulder MW
        • Thomas S
        Diagnosis and treatment of low back pain.
        BMJ. 2006; 332: 1430-1434
        • Kuhlwein A
        • Meyer HJ
        • Koehler CO
        Reduced need for diclofenac with concomitant B-vitamin therapy: Results of a double-blind clinical study with reduced diclofenac-dosage (75 mg diclofenac vs. 75 mg diclofenac plus B-vitamins daily) in patients with acute lumbago.
        Klin Wochenschr. 1990; 68: 107-115
        • Lasko B
        • Levitt RJ
        • Rainsford KD
        • Bouchard S
        • Rozova A
        • Robertson S
        Extended-release tramadol/paracetamol in moderate-to-severe pain: a randomized, placebo-controlled study in patients with acute low back pain.
        Curr Med Res Opin. 2012; 28: 847-857
        • Lee JH
        • Lee CS
        • Ultracet ER Study Group:
        A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of the extended-release tramadol hydrochloride/acetaminophen fixed-dose combination tablet for the treatment of chronic low back pain.
        Clin Ther. 2013; 35: 1830-1840
        • Levin OS
        • Moseikin IA
        [Vitamin B complex (milgamma) in the treatment of vertebrogenic lumbosacral radiculopathy].
        Zh Nevrol Psikhiatr. 2009; 109: 30-35
        • Liberati A
        • Altman DG
        • Tetzlaff J
        • Mulrow C
        • Gotzsche PC
        • Ioannidis JP
        • Clarke M
        • Devereaux PJ
        • Kleijnen J
        • Moher D
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339: b2700
        • Mao J
        • Gold MS
        • Backonja MM
        Combination drug therapy for chronic pain: a call for more clinical studies.
        J Pain. 2011; 12: 157-166
        • Mathieson S
        • Valenti L
        • Maher CG
        • Britt H
        • Li Q
        • McLachlan AJ
        • Lin CC
        Worsening trends in analgesics recommended for spinal pain in primary care.
        Eur Spine J. 2018; 27: 1136-1145
        • Mibielli MA
        • Geller M
        • Cohen JC
        • Goldberg SG
        • Cohen MT
        • Nunes CP
        • Oliveira LB
        • da Fonseca AS
        Diclofenac plus B vitamins versus diclofenac monotherapy in lumbago: the DOLOR study.
        Curr Med Res Opin. 2009; 25: 2589-2599
        • Morlion B
        Pharmacotherapy of low back pain: targeting nociceptive and neuropathic pain components.
        Curr Med Res Opin. 2011; 27: 11-33
      1. National Institute for Health and Care Excellence: Low back pain and sciatica in over 16s: assessment and management. National Institute for Health and Care Excellence. Available at: https://www.nice.org.uk/guidance/ng59. Accessed July 16, 2018.

      2. NCT00210561. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. A study of the effectiveness and safety of tramadol HCl/acetaminophen compared to placebo in treating acute low back pain Available at: https://clinicaltrials.gov/ct2/show/NCT00210561. Accessed July 16, 2018.

      3. NCT00315445. Purdue Pharma L.P. The safety and efficacy of the Buprenorphine Transdermal System (BTDS) in subjects with chronic back pain (BP96-0604). Available at: https://clinicaltrials.gov/ct2/show/NCT00315445. Accessed July 16, 2018.

      4. NCT00325949. Abbott. A study of pain relief in low back pain. Available at: https://clinicaltrials.gov/ct2/show/NCT00325949?term=NCT00325949&rank=1. Accessed July 16, 2018.

      5. NCT00679146. Sanofi. Efficacy safety of a combination thiocolchicoside + ketoprofen compared to thiocolchicoside twice a day for 7 days in patients suffering from acute non-specific low back pain (TIOKET). Available at: https://clinicaltrials.gov/ct2/show/NCT00679146. Accessed July 16, 2018.

      6. NCT01364922. AbbVie. Phase 2 chronic low back pain study. Available at:https://clinicaltrials.gov/ct2/show/NCT01364922?term+Phase+2+chronic+low+back+pain+study+rank=1. Accessed July 16, 2018.

      7. NCT02700815. Capsaicin + diclofenac gel in acute back pain or neck pain. Available at: https://clinicaltrials.gov/ct2/show/NCT02700815?term=NCT02700815&rank=12March2016. Accessed July 16, 2018.

      8. NCT02985671. To evaluate the superiority of fixed combination (orfenadrine 35 mg, acetaminophen 325 mg, caffeine 65 mg and diclofenac sodium 50 mg) compared to Voltaren® (diclofenac sodium 50 mg) in the treatment of acute postural low back pain. (Eiffel). Available at: https://clinicaltrials.gov/ct2/show/NCT02985671. Accessed July 16, 2018.

      9. NCT03003000. Ibuprofen/caffeine lower back or neck pain study. Available at: https://clinicaltrials.gov/ct2/show/NCT03003000. Accessed July 16, 2018.

      10. NCT03201393. Twice daily oral ALLOD-2 vs. placebo in the treatment of chronic low back pain (ANODYNE-4). Available at: https://clinicaltrials.gov/ct2/show/NCT03201393. Accessed July 16, 2018.

        • Ostelo RWJG
        • Deyo RA
        • Stratford PW
        • Waddell G
        • Croft P
        • Von Korff M
        • Bouter LM
        • de Vet HC
        Interpreting change scores for pain and functional status in low back pain; towards international consensus regarding minimal important change.
        Spine. 2008; 33: 90-94
        • Pareek A
        • Chandurkar N
        • Chandanwale AS
        • Ambade R
        • Gupta A
        • Bartakke G
        Aceclofenac-tizanidine in the treatment of acute low back pain: a double-blind, double-dummy, randomized, multicentric, comparative study against aceclofenac alone.
        Euro Spine J. 2009; 18: 1836-1842
        • Peloso PM
        • Fortin L
        • Beaulieu A
        • Kamin M
        • Rosenthal N
        • Protocol TRP-CAN-1 Study Group:
        Analgesic efficacy and safety of tramadol/ acetaminophen combination tablets (Ultracet) in treatment of chronic low back pain: a multicenter, outpatient, randomized, double blind, placebo controlled trial.
        J Rheumatol. 2004; 31: 2454-2463
        • Perrot S
        • Krause D
        • Crozes P
        • Naïm C
        • GRTF-ZAL-1 Study Group
        Efficacy and tolerability of paracetamol/tramadol (325 mg/37.5 mg) combination treatment compared with tramadol (50 mg) monotherapy in patients with subacute low back pain: a multicenter, randomized, double-blind, parallel-group, 10-day treatment study.
        Clin Ther. 2006; 28: 1592-1606
        • Pota V
        • Barbarisi M
        • Sansone P
        • Moraci M
        • Pace MC
        • Passavanti MB
        • Aurilio C
        Combination drug therapy with transdermal buprenorphine and pregabalin for chronic low back pain.
        Pain Manag. 2012; 2: 23-31
        • Qaseem A
        • Wilt TJ
        • McLean RM
        • Forciea M
        Noninvasive treatments for acute, subacute, and chronic low back pain: a clinical practice guideline from the American College of Physicians.
        Ann Intern Med. 2017; 147: (478-449, 2017)
        • Raffa RB
        • Pergolizzi JV
        • Tallarida RJ Jr
        Analgesic combinations.
        J Pain. 2010; 11: 701-709
      11. Review Manager (RevMan) Version 5.3. Copenhagen, The Nordic Cochrane Centre, the Cochrane Collaboration, 2014.

        • Romano CL
        • Romano D
        • Lacerenza M
        Antineuropathic and antinociceptive drugs combination in patients with chronic low back pain: a systematic review.
        Pain Res Treat. 2012; 2012154781
        • Ruoff GE
        • Rosenthal N
        • Jordan D
        • Karim R
        • Kamin M
        • Protocol CAPSS-112 Study Group
        Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter, randomized, double-blind, placebo-controlled outpatient study.
        Clin Ther. 2003; 25: 1123-1141
        • Schiphorst Preuper HR
        • Geertzen JH
        • van Wijhe M
        • Boonstra AM
        • Molmans BH
        • Dijkstra PU
        • Reneman MF
        Do analgesics improve functioning in patients with chronic low back pain? An explorative triple-blinded RCT.
        Eur Spine J. 2014; 23: 800-806
        • Shell WE
        • Charuvastra EH
        • DeWood MA
        • May LA
        • Bullias DH
        • Silver DS
        A double-blind controlled trial of a single dose naproxen and an amino acid medical food theramine for the treatment of low back pain.
        Am J Ther. 2012; 19: 108-114
        • Shell WE
        • Pavlik S
        • Roth B
        • Silver M
        • Breitstein ML
        • May L
        • Silver D
        Reduction in pain and inflammation associated with chronic low back pain with the use of the medical food theramine.
        Am J Ther. 2016; 23: e1353-e1362
        • Stafford MA
        • Peng P
        • Hill DA
        Sciatica: a review of history, epidemiology, pathogenesis, and the role of epidural steroid injection in management.
        Br J Anaesth. 2007; 99: 461-473
        • van Tulder M
        • Koes B
        • Bombardier C
        Low back pain.
        Best Pract Res Clin Rheumatol. 2002; 16: 761-775
        • Vetter G
        • Bruggemann G
        • Lettko M
        • Schwieger G
        • Asbach H
        • Biermann W
        • Bläsus K
        • Brinkmann R
        • Bruns H
        • Dorn E
        [Shortening diclofenac therapy by B vitamins. Results of a randomized double-blind study, diclofenac 50 mg versus diclofenac 50 mg plus B vitamins, in painful spinal diseases with degenerative changes].
        Z Rheumatol. 1988; 47: 351-362
        • Williams CM
        • Maher CG
        • Hancock MJ
        • McAuley JH
        • McLachlan AJ
        • Britt H
        • Fahridin S
        • Harrison C
        • Latimer J
        Low back pain and best practice care: A survey of general practice physicians.
        Arch Intern Med. 2010; 170: 271-277
        • Zhu B
        • Wang L
        • Sun L
        • Cao R
        Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis.
        J Cardiovasc Pharmacol Ther. 2012; 60: 342-346