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Methods
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Design
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Double-blinded crossover RCT |
Double-blinded RCT |
Open, controlled RCT |
Equivalence open CT |
Crossover RCT, three intervention arms |
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Country
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N/A |
United States |
India |
Japan |
Italy |
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Language
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English |
English |
English |
English |
English |
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Participants
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Mean age in years
|
42.4 (SD: ± 14.60) |
56.04 (SD: ± 10.23) |
41.5 (range: 21–65) |
72.5 (range: 65–87) |
53 ( ± SD: 16) |
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Sex: male – n (%)
|
11 (45.83) |
85 (78.7) |
109 (54,5) |
40 (66.67) |
16 (44.44) |
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Total number
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30 randomized; 24 analyzed |
108 randomized |
200 randomized |
65 randomized; 60 analyzed |
42 randomized; 36 analyzed |
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Number considered for the present systematic review
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30 randomized; 24 analyzed |
58 randomized (pain confined to the low back – Quebec I) |
93 randomized (localized CLBP) |
41 randomized; 38 analyzed (without neuropathic pain) |
20 analyzed (unlikely neuropathic component – LANSS < 12) |
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Definition of CLBP
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Chronic benign nociceptive pain. Nociceptive pain: midline lumbar back pain with tenderness over a single interspinous ligament and with pain exacerbated by flexion of the back. |
Pain ≤ T-6, secondary to degenerative disk or degenerative joint disease present “on a daily basis” for the previous 6 months or longer, of at least “moderate” intensity determined by DDS > 7. |
Backache that lasts for more than 3 months which may be localized backache, associated with radiculopathy or with lumbar canal stenosis. |
Neuropathic (Neuropathic Pain Screening Questionnaire ≥ 6) or nociceptive LBP that had been treated and followed up continuously for 3 months or longer. |
LBP with symptoms for more than 6 months, due to disc prolapse, lumbar spondylosis, and/or spinal stenosis, with minimal VAS score at recruitment of 40 mm. |
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Inclusion criteria
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Adult patients with chronic benign nociceptive pain who consented to participate in the study. The model of nociceptive pain chosen was that of posttraumatic ligamentous low back pain, defined for the purposes of the study as midline low back pain with tenderness over a single interspinous ligament and with pain exacerbated by back flexion. |
1) ages 21 to 70 years; 2) nonspecific low back pain primarily in the lumbar region, present on a daily basis for the previous 6 months or longer, adjectivally described as, of at least “mild” intensity (≥ 2 on a “0”to“10” numeric rating scale) and having an impact on 2 or more aspects of everyday life; 3) English-speaking, literate, able to understand the study, and communicate with the study team; 4) presently not a candidate for back surgery (1 prior back surgery permitted if it was less than 5 years ago); 5) agreement to discontinue muscle relaxants, antidepressants, and opioids at least 2 weeks before eligibility assessment and throughout the study (NSAIDs were permitted); and 6) if female, not pregnant or lactating, and with a negative pregnancy test at screening. |
Consecutive patients with chronic low back pain (low back pain for more than 3 months) seen at the neurology service, who were between 18 and 75 years of age. |
Patients with low back pain, aged 65 years or older, who had been treated and followed up continuously for 3 months or more at the orthopedic surgery outpatient clinic of the hospital in question. |
Patients with chronic low back pain (symptom duration: more than 6 months, mean: 13 ± 6 months) due to disc prolapse, lumbar spondylosis, and/or spinal stenosis; minimum VAS score at recruitment: greater than 40 mm; age: over 18, under 75 years; having signed the consent form to participate in the study. |
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Exclusion criteria
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Patients with symptoms of neuropathic pain (shooting pain, paresthesia/ dysesthesia, allodynia or numbness), bony pain (pain arising from spinous process rather than interspinous ligament), with abnormalities on lumbar spine X-rays (either at the site of lumbar pain or at a level from which radiation or referral of pain to that area was possible), and patients who had previously undergone any surgical procedure for their back pain. |
1) a major coexisting medical illness that might increase risks of gabapentin, or major surgical or nonsurgical intervention for any disorder within the past 12 months, because rehabilitation from treatment may confound study outcomes; 2) significant coexisting orthopedic or pain problems or back pain due to other disorders; 3) meeting DSM-IV criteria for alcohol or other substance use disorder; or current major depression or dysthymia; or lifetime diagnosis of bipolar disorder, psychosis or cognitive impairment disorder; 4) history of multiple adverse drug reactions or known allergy to gabapentin; 5) use of psychotropics, which would be continued during the study, or other drugs or agents which might interact with the study drug; 6) previous treatment with the study drug; 7) use of systemic corticosteroids or corticosteroid injections within 3 months of screening; or concurrent behavioral therapies, chiropractic treatment, or transcutaneous electrical nerve stimulation unit; 8) renal impairment; 9) hepatic impairment;10) hematologic abnormality; 11) pregnancy; and 12) use of experimental drugs or participation in other clinical trials within 2 months of screening for eligibility. |
The patients with CLBA due to specific cause such as injury, infection, malignancy, collagen vascular disease, rheumatoid or seronegative arthritis, spinal tumors and vascular malformation were excluded. Patients on immunosuppression therapy, anticancer drugs, postorgan transplantation and postspinal surgery, CLBA patients below 15 years and above 65 years of age, those with pregnancy, lactation and severe neurological deficit due to radiculopathy or lumbar canal stenosis were excluded. |
Patients who received other treatment for LBP, patients whose lower extremity symptoms were stronger than their low back pain, and patients with thoracolumbar compression fractures, tumorous infections of the spine, symptomatic lumbar disc herniation, spondylolisthesis ≥ grade II, and dementia. |
Previous back surgery; diabetes; neurological disease; cardio-renal disease; history of gastric ulcers or intestinal bleeding; known allergy to the drugs under study; alcohol or drug abuse. |
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Interventions
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Intervention group
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Initial daily dose of 300 mg, increasing in 300 mg steps at weekly intervals to receive a total daily dose of 15 mg/kg/day gabapentin to the nearest 300 mg. |
Gabapentin 300 mg orally 3 times a day up to a maximum of 1,200 mg orally 3 times a day for 12 weeks. |
AMT 12.5 mg at bedtime for 2 weeks, followed by 25 mg for 4 weeks, then increased to 50 mg. |
PG 75 mg before bedtime for 4 weeks. |
Celecoxib (approximately 3–6 mg/kg/day) + placebo; PG (approximately 1 mg/kg/day the first week and then 2–4 mg/kg/day) + placebo; celecoxib (approximately 3–6 mg/kg/day) + PG (approximately 1 mg/kg/day the first week, and then 2–4 mg/kg/day). Each treatment lasted 4 weeks, with one week of discontinuation between treatments. |
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Control group
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Placebo with an increase in the number of capsules proportional to the equivalent increase in gabapentin capsules, for 6 weeks. |
Inert placebo capsules identical in size and shape to the experimental capsules, one to three capsules taken orally three times daily for 12 weeks. |
PG 75 mg twice daily for 2 weeks, followed by 150 mg twice daily for 4 weeks, then 300 mg twice daily. |
TRAM/APAP twice-daily dosing (2 tablets per day; tramadol 75 mg and acetaminophen 650 mg per day) for 4 weeks. |
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Follow-up (weeks)
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13 (6 weeks in each treatment period, followed by a 1-week washout phase). |
12 |
14 |
4 |
15 (4 weeks in each treatment period with 1 week of washout between each one). |
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Specific drop-out rates
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Of the 30 patients originally recruited, 4 did not show up for review, one failed to complete the study record sheets, and one withdrew early due to gabapentin side effects. |
Of the patients who dropped out before completing 12 weeks, 19 had been assigned to gabapentin and 17, to placebo. The main reason for discontinuation was similar in both groups and, in most cases, it was due to adverse effects or lack of efficacy; a considerable proportion were lost to follow-up, and no reason could be obtained for withdrawal. |
15 patients in each study arm were lost to follow-up for unknown reasons; 11 patients in the AMT group and 12 in the PG group discontinued the intervention because of side effects. |
2 patients in the PG group and 3 in the TRAM/APAP group discontinued the intervention due to side effects. No patient was lost to follow-up during the study. |
4 out of 42 recruited patients discontinued treatment within the first 2 weeks due to adverse events (epigastralgia and/or nausea), 1 taking PG monotherapy, 1 taking celecoxib monotherapy, and 2 taking PG + celecoxib. Of the 38 remaining participants, another 2 also discontinued treatment (1 for logistical reasons at work, the other, for trauma due to a car accident). |
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Outcomes
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Primary
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Analgesic efficacy (mean pain score of patients and controls, on a scale of 0 to 10), mobility (mean mobility score – ability to flex the back, on a scale of 0 to 10, self-reported by the patient), analgesic consumption and patient preference for study medication. |
Transformed DDS-pain intensity scores adjusted for time (time frame: baseline to week 12 with interim measurements at weeks 1, 2, 3, 4, 5, 7, and 9). |
Mean pain reduction (VAS score reduction > 50%) after 14 weeks. |
Pain, assessed using the VAS (scale from 0 to 10) and activities of daily living, assessed using the RMDQ, Short-Form McGill Pain Questionnaire, EuroQol quality-of-life scale, and Geriatric Depression Scale. |
Mean pain reduction after different treatment regimens by the VAS (100 mm). |
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Secondary
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RMDQ adjusted for time (time frame: baseline to week 12 with interim measurements at weeks 1, 2, 3, 4, 5, 7, and 9). |
Improvement in disability > 20% and improvement of adverse effects after 14 weeks. |
Adverse effects due to the treatments. |
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Results considered for the present systematic review
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Efficacy
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Gabapentin: mean pain scale dropped from 7.10 (95%CI: 6.26–7.94) to 6.39 (95%CI: 5.39–7.39) (p < 0.05). Placebo: no significant decrease in mean pain, from 7.52 (1.94) to 7.13 (2.34). Gabapentin: mean mobility increased from 4.65 (95%CI: 3.84–5.46) to 5.46 (95%CI: 4.50–6.42) (p < 0.01). Placebo: non-significant decrease in mean mobility, from 5.07 (2.08) to 5.05 (2.04). |
ITT: decrease in DDS both in the gabapentin and in the placebo groups (p < 0.0001), with a reduction of about 30% on DDS and no difference between the interventions (p = 0.423). Per-protocol analysis: reduction in pain using a standard verbal numerical rating scale from 0 to 10 in both groups (5.8 to 3.5 and 5.7 to 4.1; p < 0.0001), with no significant difference between the groups (2.2 versus 1.6; p = 0.253). |
ITT: for the outcome reduction of pain intensity in the VAS reported by the participant of 50% or more, we obtained values of 32.6% (15 of 46) and 53.2% (25 of 47) (0.61 [95%CI: 0.37–1.01]; p = 0.05) for the PG and AMT groups respectively. As for the functionality analysis, ODI reduction greater than 20%, we obtained values of 39.1% (18 of 46) and 65.96% (31 of 47) (0.59 [95%CI: 0.39–0.90]; p = 0.01) for the PG and AMT groups respectively. |
Pain improvement in the VAS (scale from 0 to 10), there was significant improvement after 4 weeks in both groups (p < 0.05 for both); however, in the TRAM/APAP group, this improvement could already be observed after 2 weeks (p < 0.05). As for the functional improvement by the RMDQ, no significant improvement was noted for the PG group, whereas for the TRAM/APAP group, a significant improvement was observed after 2 weeks of administration. |
PG versus celecoxib: only celecoxib has been shown to improve pain score by VAS (43.8 [SD: ± 12.9] to 32.5 [SD: ± 15.5]; p = 0.01). PG + celecoxib versus PG: greater decrease in pain with the combined use of drugs (45.1 [SD: ± 14.2] to 32.9 [SD: ± 13.9] versus 49.4 [SD: ± 13.2] to 50.7 [SD: ± 13.8]; p = 0.0002). PG + celecoxib versus celecoxib: no superiority of the combined regimen compared to monotherapy in reducing pain (45.1 [SD: ± 14.2] to 32.9 [SD: ± 13.9] versus 43.8 [SD: ± 12.9] to 32.5 [SD: ± 15.5]; p = 0.9). |
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Safety
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Adverse events were reported in both groups, with a significantly higher number during the gabapentin use (9 out of 30), versus placebo (2 out of 30) (4.5 [95%CI: 1.06–19.11]; p = 0.04). |
At least 1 adverse event: gabapentin – 49 out of 55 (89%) versus placebo – 35 out 53 (66%); p = 0.008. At least 1 moderate to severe adverse event: gabapentin – 30 out of 55 (55%) versus placebo – 17 out of 53 (32%); p = 0.03. No serious adverse events were reported. |
Adverse events were reported in both groups, with no significant differences between them (18 patients in the AMT and 21 in the PG group; p = 0.48). |
Adverse events were reported in both groups, with a significantly higher number in the group that was given TRAM/APAP (21 out of 33), versus PG (12 out of 32) (0,59 [95%CI: 0.35-0.99]; p = 0.04). |
4 patients out of 42 recruited discontinued treatment due to adverse events (epigastralgia and/or nausea): 1 taking PG; 1 taking celecoxib; 2 taking PG + celecoxib. |
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