Low Back Pain Medical Monotherapies

Drug Therapies

NSAIDs

• CLBP: Mean pain reduction -3.3 on a 0 to 100 scale for CLBP.
• ALBP: Mean pain reduction difference -7.3 on a 0 to 100 scale for ALBP.
• Function: Small benefit of -0.85 on a 0 to 24 scale for CLBP.
• 12 weeks statistically the same to 4 weeks.
• Home based exercise superior for function but similar for pain

Muscle Relaxants

• Shaheed 2016 – 15 eligible RCTs, significant short term relief for nonbenzodiazepines for acute (but not chronic) pain, but no improvement in disability. No benefit for benzodiazepines.
• Orphenadrine, baclofen, and dantrolene research didn’t meet inclusion criteria. One positive study for tetrazepam in 1990 for reducing “muscle spasm” but the study is not on the internet and we don’t have that in NZ anyway
• Cochrane 2003 - 24 studies (various benzos, nonbenzos, and antispasticity relaxants). Effective for acute back pain 0.80 relative risk at 5-7 days, and 0.7 at 10-14 days.
• Friedman 2018 – Orphenadrine + naproxen not superior to placebo + naproxen for disability and pain.
• The longest follow up I found was 30 days Tinzanidine vs Epirisone Rossi 2013
• None of the muscle relaxants on the NZ formulary as of June 2020 had evidence that met the inclusion criteria of the Shaheed 2016 metaanalysis.

Opioids

• Small short term benefit in pain (SMD -0.43)
• No benefit for long acting opioids
• Opioids not superior to non-opipids at 12 months for chronic back, hip, and knee pain, with more side effects in non blinded trial.
• No benefit compared to NSAIDs or antidepressants
• Small benefit (SMD -0.26) in the short term in CLBP
• Worse pain in the long term in a mixed pain condition study
• Aberrant drug taking behaviours in up to 24% of CLBP
• Tramadol - No benefit when only assessing registered and pre-registered trials

Antidepressants

• Duloxetine
  • 4 x 12 week RCTs showed benefit vs placebo (n=1,295)
  • Average <1 point improvement on 0-10 scale
  • 11.9% had >30% pain reduction
  • Responders tended to have early pain reduction at 2 weeks (≥15%), ≥ 2 pain sites, be female
  • Not available in NZ
• Venlafaxine
  • No RCTs, Only one positive non controlled trial for both depression and CLBP
• TCAs
  • Possible benefit for pain (modest) but not function, but there are only find systematic reviews, no meta-analysis.
• Gabapentinoids
  • Not effective for CLBP, chronic radiculopathy, or as an adjunct to another analgesic. One of the large well known studies was in NEJM

Drug Therapies Bottom Line

• Low to moderate quality evidence that NSAIDs may have a small benefit for acute and chronic pain and function, and early response is predictive of later response
• Low quality evidence that a couple of non-benzodiazepine muscle relaxants may be effective for ALBP but aren’t available in NZ
• Low quality evidence that strong opioids have a small benefit for pain and function in the short term, but cause increased pain and addiction in the longer term.
• Moderate quality evidence that the antidepressant Duloxetine may be effective for CLBP
• Unclear role of TCAs
• Moderate quality evidence that gabapentinoids are likely not effective for CLBP or radicular pain, either in isolation or as an adjunct.
• Editorial in 2013 BMJ – No single drug will treat more than a minority of patients, but failure with one drug does not mean to expect failure with others, even within a class. Success or failure can be determined within 2-4 weeks. However evidence is still limited.

Injection Therapies

Epidural Steroid Injections

• Probably slightly reduce leg pain and disability in the short term, 25 trials, evidence quality moderate.
• MD may not be clinically significant at less than 10%
• Leg pain: MD -4.93 (0 to 100 scale) at 2 weeks to 3 months
• Disability: MD -4.18 (0 to 100 scale) at 2 weeks to 3 months
• Apparently some controversy as to trial selection in the Cochrane metaanalysis.
• For back pain, probably no effect
• Bogduk in 2002 said there were issues at the time of trials mixing up radicular pain and back pain but they seem to be well separated in the Cochrane 2020 meta-analysis.

Tender Point Injections

Malanga and Wolff in 2008 describe the technique as follows: " It described holding the syringe in the dominant hand while palpating the trigger with the thumb or index finger of the opposite hand. Needle insertion was into the subcutaneous tissue adjacent to the TrP at a 50 to 70 angle to the skin aiming at the taut band. Multiple insertions in different directions from the subcutaneous layer were ‘‘fast in’’ and ‘‘fast out’’ to probe for latent triggers. Each thrust coincided with the injection of 0.02 to 0.05 mL of injectate to a total of 0.5 to 1 mL in each TrP. Compression of the point for 2 minutes allowed hemostasis, which was followed by stretching of the muscle. They noted that the best responses to injection were found when the ‘‘local twitch response’’ was provoked by impaling the active point "

• Possibly effective in the short term.
  • Kocak 2018: TPI superior to i.v. NSAID at 60 mins for acute back pain
  • Garvey 1989: TPI at least as effective as cold spray + acupressure
  • Malanga 2008: Narrative review, limited evidence beyond the short term.
  • It is interesting to note that the saline often used as a control in trials may contain (unless preservative-free) 0.9% benzyl alcohol

• Total Dorsal Rami Block
  • Miyakoshi 2007: bilateral L4/5 total dorsal rami block (5mL each side mepivacaine) by CT better than TPI at 7 days for CLBP in elderly.
  • They note "The facet joints, back muscles, fascia, ligaments, and skin of the low back region are all innervated by the medial, intermediate, and/or lateral branches of the lumbar dorsal rami. Each dorsal ramus of the lumbar spinal nerve divides into three branches: medial, intermediate, and lateral branches [10,11] (Fig. 1). These three branches principally innervate three major longitudinal back muscles: multifidus, longissimus, and iliocostalis, respectively [10,11]. Furthermore, deep to multifidus, articular branches from the medial branch innervate the facet joints above and below theoretically, all the low back pains originating from myofascial structures [1], facet joint [9,12,13], or both should be alleviated by blocking all three branches of the lumbar dorsal ramus. They confirmed spread over both adjacent branches using contrast of medial branches plus intermediate and lateral branches"

Prolotherapy

• Nonspecific low back pain – probably not effective
  • Cochrane 2007 (5 studies) concluded that prolotherapy alone is not effective for chronic low back pain. However 4/5 studies used a mixture dextrose-glycerine-phenol and no specific diagnosis
  • Best study Yelland 2004: n=110 CLBP, 20% dextrose/lignocaine repeated over 6 months, 2 year follow up, significant improvements in pain and disability but no different to saline Cochrane 2007, Yelland 2004. At 12 months, the proportions achieving more than 50% reduction in pain from baseline by injection group were glucose-lignocaine: 0.46 versus saline: 0.36 they also randomised to do flexion/extension exercises and there was no benefit.
• Sacroiliac Joint Pain
  • 1 x positive study. prolotherapy vs steroid (intraarticular), n = 48
  • Inclusion: sacroiliac joint pain >3 months, confirmed by fluoroscopic block (pain decrease of 50%). Pain just below PSIS and positive Patrick or Gaenslens test and pain reduction >50% with bupivacaine injection fluoroscopic
  • Exposure: 2.5mL of 25% dextrose with bupivacaine into SI joint (fluoroscopically) every two weeks up to three times until pain relief at least 90%.
  • Control: same but with triamcinolone 40mg
  • Results: Significant sustained improvements for prolotherapy
• Botox
  • May provide partial relief of pain, with no data beyond 2 months
  • Three studies, with Foster et al being the best one. The other two have significant problems.
  • Cost is $1100 for 2 vials (200 units) for the dose used in Foster et al study. Not covered by ACC or Southern Cross for this indication.

Injection Therapies Bottom Line

• Epidural Steroid Injections
  • Low to moderate quality evidence that probably works for radicular leg pain but effect size may not be clinically significant.
  • They generally don’t have a role for back pain.
• Tender Point Injections
  • low quality evidence that effective in the short term for acute pain.
  • Interesting concept of total dorsal rami blocks.
• Prolotherapy
  • low quality evidence that effective in the short and long term for sacroiliac joint pain (intraarticular injections).
  • Unclear if it is effective for other causes of back pain.
• Botox
  • low quality evidence that effective in the short term

Surgery

Placebo Controlled Surgery Trials

• Astoundingly few placebo controlled trials (i.e. sham studies) in all of orthopaedic surgery. All no difference
  • Bradley 2002: tidal irrigation v placebo for knee OA
  • Moseley 2002: lavage/debridement v placebo for knee OA
  • Kallmes 2009: vertebroplasty v placebo
  • Buchbinder 2009: vertebroplasty v placebo
  • Kroslak 2013: debridement v placebo for lateral epicondylitis
• The remaining RCTs are all non-placebo controlled, i.e. comparing surgery A to surgery B, or surgery A to physiotherapy.

Discectomy for Sciatica

• Sciatica lasting 4-12 months
  • Bailey 2020: microdiscectomy superior to nonoperative care (incl. epidural injection) with surgery if needed for pain with 1 year follow up. (pain difference 2.4 scale 0 to 10). At 6 months, the score for leg-pain intensity was 2.8±0.4 in the surgical group and 5.2±0.4 in the nonsurgical group
  • At 1 year, the leg-pain intensity score was 2.6±0.4 in the surgical group and 4.7±0.4 in the nonsurgical group;

the ODI score was 22.9±2.3 and 34.7±2.4,

• Sciatica lasting 6 to 12 weeks
  • Peul 2008: Surgery conferred more rapid relief of pain, but the benefit was not sustained at 6, 12, and 24 months. 20% reported unsatisfactory outcome at 2 years.
  • Osterman 2006: Surgery more rapid initial recovery, but no difference at 6 weeks with 2 year follow up. Subgroup analysis discectomy superior if herniation at L4/5 (needs verification)

• Sciatica lasting “at least 6 weeks”
  • Weinstein 2006: ~80% pain less than 6 months. Major crossover issues. Intent-to-treat both improved. Advantage of surgery in as-treated analysis, worse outcome in post-hoc analysis if >6 months. Significant advantage for non-workers compensation group

Spinal Stenosis Surgery - Surgery vs non operative management

• Cochrane 2016: 5 RCTs. Studies low quality. “We have very little confidence to conclude whether surgical treatment or a conservative approach is better for lumbar spinal stenosis”.
• Weinstein 2008 (SPORT): n=289. Significant nonadherence and crossover. Surgery vs nonoperative. Intention to treat showed improvement in pain in surgery group but not disability. 2 year follow up. As treated analysis showed improvement in all outcomes in surgery group.
• Malmivaara 2007: n=94. Surgery (segmental decompression and an undercutting facetectomy) vs nonoperative. Surgery superior but benefits diminished overtime with both groups improving. 2 year follow up.
• Brown 2012: n=38, mild decompression vs epidural steroid. At 6 weeks epidural better for function (claudication questionnaire), but worse for VAS. Significant crossovers at 12 weeks preventing further analysis.

Spinal Stenosis - Decompression plus fusion vs decompression-alone

• Forsth 2016: n=247, decompression surgery equal to decompression plus fusion with 5 years of follow up. (pain and disability)
• Ghogawala 2016: n=66 with grade I spondylolisthesis, fusion better than decompression (“physical quality of life”) by year 2 (but not by year one). Nut no improvement in disability score.
• Cochrane 2016: Newer techniques are not superior to decompression. Didn’t include above two studies.
• Chang 2017: meta-analysis (15 studies) including the above newer studies, no benefit for decompression plus fusion over decompression alone at 2 years. Fusion has higher risk of complications. “We believe decompression alone to be a sound choice for LSS”

Fusion for Non-Specific CLBP

• Harris 2018:
  • Analysis of 33 meta-analyses mostly of 4 non-placebo controlled RCTs (!). Fritzell 2001, Brox 2003, Fairbank 2005, Brox 2006.
  • The most recent moderate quality review (Chou 2009): not more effective than intensive rehabilitation.
  • None of the post 2009 trials was of sufficiently high quality to change this conclusion
  • Complications are common at 16%
• Mannion 2013
  • Long term follow up (8-11 years) of the three classic RCTs Fritzel, Brox, Fairbank
  • Surgery no better than CBT and exercise both intention-to-treat and as-treated.
  • Findings mirror the two years results (Swedish study outlier but reporting bias and less effective non-operative treatment)
  • Just 50-60% of patients in each group reported their back was better/much better.
  • Just 40% had disability scores in the normal range
  • 25% crossover
  • Swedish trial the outlier, they reported positive outcomes at 2 years, but no difference at 10 years. But significant reporting bias using “global assessment” as the reported measure Non operative treatment was unstructured, nonspecific physiotherapy
• Good Editorial 2016 Spine Mannion
  • ITT analyses may be supported by analyses in which cases are grouped as “per protocol” (those who underwent the treatment to which they were assigned and completed all the follow-ups) or “as treated” (the treatment actually received) or “worst case” (group crossovers considered as “failing” the treatment to which they were randomized). These subgroup analyses present their own problems. Patients moving from non-operative to surgical treatment can be tracked with relative ease, but not those having surgery, failing it, and then going on to have successful non-operative treatment. Any subgrouping based on group changes in one direction only and on the assertion that a group change from non-operative to surgery indicates failure of non-operative treatment but revision surgery does not count as failure of surgery will inevitably be biased
• Mino 2017: Cohort study, 95% of those on opioids preoperatively continued on them postoperatively with 2 year follow up.
• Surgeries: posterolateral fusion in Norway, up to surgeon in UK studies
• There is no evidence that surgery undertaken without a valid diagnosis is effective for chronic low back pain
  • Brox 2003: Eligibility CLBP >1 year, and degeneration L4/5 and/or L5/S1 on XR.
  • Fritzell 2001: Eligibility severe CLBP >2 years, back>leg pain, clinician should interpret pain arising from L4/5 and/or L5/S1 using history/exam/radiology, major disability >1 year, degenerative change at above levels
  • Fairbank 2005: eligible if patient/surgeon uncertain which treatment best, >1 year CLBP
  • It is unclear whether discography is useful for patient selection Harris 2018

Lumbar Disc Replacement

• Hellum 2011
  • Lumbar disc prosthesis v rehabilitation, 2 year follow up
  • Statistically significant benefit for surgery
  • Disability: less than clinically significant benefit at 8 points on 0 to 100 scale.
  • Pain: 12 point difference favouring surgery.
  • only study comparing with rehab
• Cochrane 2013
  • Systematic review comparing disc replacement v fusion
  • No blinding and bias with sponsorships.
  • Statistically significant but not clinically significant benefit for replacement
  • Prevention of adjacent level disease and/or facet disease was not properly assessed.
• Not really done in NZ

Surgery Bottom Line

• There are no placebo controlled trials for any spinal surgery, below all low quality evidence
• Microdiscectomy for Sciatica
  • Possibly effective if pain 4 – 12 months [LOE 1c]
  • If done early then possibly more rapid recovery but no difference by 6 weeks.
• Spinal Stenosis Surgery
  • Possibly effective but benefits diminish over time
  • The addition of fusion to decompression is probably not necessary, and adds significant extra complications.
• Fusion for CLBP
  • No more effective than intensive rehabilitation
  • Possibly more effective than non-intensive rehabilitation, but benefits not sustained.
  • Disc Replacement for CLBP
  • Possibly statistically but no clinically significant benefit for surgery over non-intensive rehabilitation
  • No more effective than fusion

Spinal Cord Stimulation

Spinal cord stimulation involves placement of electrodes in the epidural space adjacent to the spinal area presumed to be the source of pain. An electric current is then applied to achieve sympatholytic and other neuromodulatory effects. The number and type of electrode leads and parameters of electrical stimulation can vary They may be implanted percutaneously or by laminectomy. Power is supplied by implanted battery or transcutaneously through an external radiofrequency transmitter. Implantation is a two stage process. A trial is performed, followed by permanent implantation for successful trials. High frequency/burst stimulation associated with greater benefit than conventional SCS. The pain-suppressing effect of SCS is likely related to a combination of a spinal and supraspinal mechanism (2, 31). The spinal mechanism involves antidromic activation of ascending dorsal column fibers, but SCS might also interact via orthodromic ascending fibers with descending serotoninergic pain modulatory systems. Kirketeig 2019: good overview of the research

Tonic Stimulation

• North 2005: n=50, persistent pain after surgery with leg pain greater or equal to back pain. SCS superior to reoperation for achieving >50% pain relief (38% v 12%)
• Kumar 2007: n=100, persistent radicular pain following surgery for herniated disc. SCS superior to “conventional medical management” for pain (48% v 9%)
• 26-32% in these RCTs experienced a complication. Electrode migration, infection, generator pocket-related complications, and lead problem.
• Only been studied in Failed Back Surgery Syndrome. Turner 2010: prospective cohort study, workers compensation, no previous surgery. outcomes at 12 and 24 months no better than pain clinic management.
• No RCTs done for primary back pain. North 2005 patients had improvement in both leg and back pain.
• No placebo controlled trials for tonic stimulation, because it is impossible, because it causes paraesthesias.

Burst Stimulation

• Doesn't cause paraesthesias so can perform placebo controlled tirals
• De Ridder 2013: placebo controlled RCT, n=15, intractable back and limb pain. 12/15 were failed back surgery syndrome. Burst mode effective for back/limb and reducing attention to pain, tonic mode effective only for limb pain. 4 week follow up
• Schu 2014: placebo controlled RCT, n=20, FBSS with pre-existing SCS, burst stimulation superior to tonic. 3 week follow up
• Tjepkema-Cloostermans 2016: placebo controlled RCT, n=40, FBSS with pre-existing SCSS, high/low amplitude burst stimulation superior to tonic
• Deer 2017: RCT (non-placebo controlled), n=100, FBSS plus other conditions, burst superior to tonic, but 24% preferred tonic. 1 year follow up. Designed under FDA guidance.

Attenuation

• RCTs longest follow up is 3 years
• Nissen 2018: prospective trial of 20 years of consecutive patients, average follow up was 6 years of 224 consecutive FBSS patients.
• 75% who received a SCS after a trial period continued to use it throughout the follow up period which was 18 years in some patients

SCS Bottom Line

• This is a palliative treatment (improvement in pain but generally not function)
• It should only be considered for those with
  • Predominant radicular pain PLUS
  • “Failed back surgery syndrome” PLUS
  • Clear anatomical source of pain PLUS
  • No abnormal illness behaviour PLUS
  • A positive trial period with an external device
• There is a significant complication rate
• Burst stimulation is superior to tonic stimulation for most patients
• Extremely expensive with limited availability in NZ
• The evidence may change as technology improves

Intraspinal Opioids

• No RCTs for any non cancer pain condition after 30 years of use. $30,000 - $40,000 USD, with refills costing $500/visit in 2014
• Turner 2007 (systematic review): 41% had urinary retention, 37% required catheterisation, nausea/vomiting 33%, pruritis 26%, catheter related complications 18%, pump malposition 17%, wound infection 12%, meningitis 3%
• Loeser 2014 (Editorial):
  • Very little information on the proper selection of patients
  • Most studies show that those on high-dose opioids without relief are poor candidates
  • Dose escalation and side effects occur with any route of delivery
  • Multidisciplinary pain management is more effective and cheaper
  • May be considered for palliative care. Smith 2002: n=202, RCT, refractory cancer pain (not only back pain). Success in 84.5% vs 70.8% for comprehensive medical management.

Intrathecal Opioids Bottom Line

No valid use in the realm of Musculoskeletal Medicine.

See Also

Low Back Pain Nonmedical Monotherapies Precision Techniques