Table 1.

Table 1 Clinical trials on combination pharmacological therapy of chronic low back pain.

Reference	Trial design	Duration	Main inclusion/exclusion criteria	Pain type	Intervention(s) and dose	Principal outcome
L. Romanò et al. [31]	Prospective, randomized, 3-way cross-over study 4-weeks treatment with each therapy	12 week	18–75 years Chronic LBP for >6 months due to disc prolapse, lumbar spondylosis, and/or spinal stenosis Minimum VAS >40 mm (on a scale of 0–100 mm) Patients with neurological disease excluded	Mixed	Celecoxib 3–6 mg/kg/die + placebo (n = 36) and Pregabalin 1 mg/kg/die for the first week, then 2–4 mg/kg/die + placebo (n = 36) and Celecoxib 3–6 mg/kg/die + pregabalin 1 mg/kg/die for the first week, then 2–4 mg/kg/die (n = 36)	Combination therapy was more effective than either monotherapy for mean pain reduction (assessing using 0–100 mm VAS)
Gatti et al., [32]	Prospective, observational, and open-label study	6 week	Chronic LBP (46 months) Moderate to severe (>3 on a 0–10 VAS) Pain not responsive to previous systemic or local analgesic treatment	Osteoarticular, nociceptive pain (Group A) or neuropathic pain (Group B)	Group A Previous treatment discontinued: Oxycodone 5 mg + paracetamol 325 mg/8 hours (n = 78) Group B Previous treatment (except gabapentin). Fixed combination of oxycodone 5mg + paracetamol 325 mg/8 hours (n = 72)	Group A 73.9% and 78.3% (assessed using 0–10 VAS), respectively Group B All patients reported improved or stable neuropathic pain symptoms except pain preventing sleep
Pota et al., [33]	Prospective, observational, and open-label study	2 month	Chronic LBP (33 months)	Mixed	(n = 22) Month 1: Buprenorphine TDS 35 μ g/ml Month 2: Buprenorphine TDS 35 μ g/ml + pregabalin 150 mg or Buprenorphine TDS 35 μ g/ml + placebo	Significant reductions in pain(assessed using 0–100 VAS) were observed after month 1 (P < 0.01) Significant reductions in painafter month 2 were only observed in the combination group (P < 0.01)
Khoromi et al., [34]	Single-centre, cross-over, randomized trial	9 week	18–65 years Lumbar radiculopathy Average leg pain score >4 (0–10 cm VAS) Patients with polyneuropathy and peripheral vascular disease associated with symptoms of numbness, or patients with burning painin the lower extremities, were excluded	Neuropathic	(n = 61) Morphine 15–90 mg and Nortriptyline 25–100 mg and Morphine 15–90 mg nortriptyline 25–100 mg	No significant reductions in mean leg pain (assessed using 0–10 VAS) or other leg or back pain were observed in any treatment group Pain reduction relative to placebo was 14% for nortriptyline, 7% for morphine, and 7% for combination therapy
Peloso et al., [35]	Multi-centre, randomized, double-blind study	21-day washout period, 91-day double-blind treatment period	> 18 years Chronic LBP Pain intensity >40 (0–100 mm VAS) Patients with neurologic deficits in lower extremities, symptomatic disk herniation, severe spinal stenosis, or spondy lolisthesis excluded	Nociceptive	Tramadol 37.5–300 mg + paracetamol 325–2600 mg (n = 167) or Placebo (n = 169)	Mean final pain intensity scores (assessed using 0–100 mm VAS) were significantly lower with combination therapy (47.4) than with placebo (62.9; <0.001), as were mean final pain relief scores (assessed on 6-point Likertscale: 1.8 and 0.7, resp., P < 0.001)
Ruoff et al., [36]	Multi-centre, randomized, double-blind, parallel group study	21-day washout period, 10-day titration period, 81-day treatment period	25–75 years Chronic LBP Pain intensity >40 (0–100 mm VAS)	Mixed	Tramadol 37.5–300 mg + paracetamol 325–2600 mg (n = 161) OR Placebo (n = 157)	Significantly lower final meanpain score (assessed by 0–100 mm VAS) with combination therapy than with placebo (P < 0.015)
CR=controlled release; LBP: low back pain; Mixed: mixed nociceptive and neuropathic pain; TDS: Transdermal delivery system; VAS: visual analogue scale.