The Efficacy, Adverse Events, and Withdrawal Rates of the Pharmacological Management of Chronic Spinal Cord Injury Pain: A Systematic Review and Meta-Analysis

Canavan, Clare; Inoue, Takayoshi; McMahon, Sinéad; Doody, Catherine; Blake, Catherine; Fullen, Brona M.

doi:10.1093/pm/pnab140

Cited by 8 publications

(12 citation statements)

References 70 publications

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“…Sensitivity analysis was conducted by excluding studies rated as high risk of bias, excluding a trial of Namisol ®38 (purified plant-based dronabinol) that was grouped with synthetic dronabinol, and by repeating analyses using a random effects model based on the profile likelihood method with the Bartlett's correction to reduce potential deviation from the null distribution when the number of studies is small. 39 All meta-analyses were conducted using command metan and admetan in Stata/SE 16.1 (StataCorp, College Station, TX). Publication bias (small study effect) was assessed using both funnel plots and the Egger test when there were eight or more studies included in a meta-analysis.…”

Section: Data Synthesis and Analysismentioning

confidence: 99%

Living Systematic Review on Cannabis and Other Plant-Based Treatments for iii Chronic Pain: 2022 Update

Chou¹,

Wagner²,

Ahmed³

et al. 2022

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Objectives. To update the evidence on benefits and harms of cannabinoids and similar plant-based compounds to treat chronic pain using a living systematic review approach. Data sources. Ovid® MEDLINE®, PsycINFO®, Embase®, the Cochrane Library, and SCOPUS® databases; reference lists of included studies; and submissions received after Federal Register request were searched to April 4, 2022. Review methods. Using dual review, we screened search results for randomized controlled trials (RCTs) and observational studies of patients with chronic pain evaluating cannabis, kratom, and similar compounds with any comparison group and at least 1 month of treatment or followup. Dual review was used to abstract study data, assess study-level risk of bias, and rate the strength of evidence (SOE). Prioritized outcomes included pain, overall function, and adverse events. We grouped studies that assessed tetrahydrocannabinol (THC) and/or cannabidiol (CBD) based on their THC to CBD ratio and categorized them as comparable THC to CBD ratio, high-THC to CBD ratio, and low-THC to CBD ratio. We also grouped studies by whether the product was a whole-plant product (cannabis), cannabinoids extracted or purified from a whole plant, or a synthetic product. We conducted meta-analyses using the profile likelihood random effects model and assessed between-study heterogeneity using Cochran’s Q statistic chi square test and the I2 statistic. Magnitude of benefit was categorized as no effect or small, moderate, and large effects. Results. From 3,283 abstracts, 21 RCTs (N=1,905) and 8 observational studies (N=13,769) assessing different cannabinoids were included; none evaluated kratom. Studies were primarily short term, and 59 percent enrolled patients with neuropathic pain. Comparators were primarily placebo or usual care. The SOE was low unless otherwise noted. Compared with placebo, comparable THC to CBD ratio oral spray was associated with a small benefit in change in pain severity (7 RCTs, N=632, 0 to10 scale, mean difference [MD] −0.54, 95% confidence interval [CI] −0.95 to −0.19, I2=39%; SOE: moderate) and overall function (6 RCTs, N=616, 0 to 10 scale, MD −0.42, 95% CI −0.73 to −0.16, I2=32%). There was no effect on study withdrawals due to adverse events. There was a large increased risk of dizziness and sedation, and a moderate increased risk of nausea (dizziness: 6 RCTs, N=866, 31.0% vs. 8.0%, relative risk [RR] 3.57, 95% CI 2.42 to 5.60, I2=0%; sedation: 6 RCTs, N=866, 8.0% vs. 1.2%, RR 5.04, 95% CI 2.10 to 11.89, I2=0%; and nausea: 6 RCTs, N=866, 13% vs. 7.5%, RR 1.79, 95% CI 1.19 to 2.77, I2=0%). Synthetic products with high-THC to CBD ratios were associated with a moderate improvement in pain severity, a moderate increase in sedation, and a large increase in nausea (pain: 6 RCTs, N=390, 0 to 10 scale, MD −1.15, 95% CI −1.99 to −0.54, I2=48%; sedation: 3 RCTs, N=335, 19% vs. 10%, RR 1.73, 95% CI 1.03 to 4.63, I2=28%; nausea: 2 RCTs, N=302, 12.3% vs. 6.1%, RR 2.19, 95% CI 0.77 to 5.39; I²=0%). We also found moderate SOE for a large increased risk of dizziness (2 RCTs, 32% vs. 11%, RR 2.74, 95% CI 1.47 to 6.86, I2=40%). Extracted whole-plant products with high-THC to CBD ratios (oral) were associated with a large increased risk of study withdrawal due to adverse events (1 RCT, 13.9% vs. 5.7%, RR 3.12, 95% CI 1.54 to 6.33) and dizziness (1 RCT, 62.2% vs. 7.5%, RR 8.34, 95% CI 4.53 to 15.34); outcomes assessing benefit were not reported or insufficient. We observed a moderate improvement in pain severity when combining all studies of high-THC to CBD ratio (8 RCTs, N=684, MD −1.25, 95% CI −2.09 to −0.71, I2=58%; SOE: moderate). Evidence (including observational studies) on whole-plant cannabis, topical or oral CBD, low-THC to CBD, other cannabinoids, comparisons with active products or between cannabis-related products, and impact on use of opioids was insufficient to draw conclusions. Other important harms (psychosis, cannabis use disorder, and cognitive effects) were not reported. Conclusions. Low to moderate strength evidence suggests small to moderate improvements in pain (mostly neuropathic), and moderate to large increases in common adverse events (dizziness, sedation, nausea) with high- and comparable THC to CBD ratio extracted cannabinoids and synthetic products during short-term treatment (1 to 6 months); high-THC to CBD ratio products were also associated with increased risk of withdrawal due to adverse events. Evidence for whole-plant cannabis and other comparisons, outcomes, and plant-based compounds was unavailable or insufficient to draw conclusions. Small sample sizes, lack of evidence for moderate and long-term use and other key outcomes, such as other adverse events and impact on use of opioids during treatment, indicate that more research is needed.

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Section: Data Synthesis and Analysismentioning

confidence: 99%

Living Systematic Review on Cannabis and Other Plant-Based Treatments for iii Chronic Pain: 2022 Update

Chou¹,

Wagner²,

Ahmed³

et al. 2022

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“…Advances in research and technology have provided optimism for SCI patients in terms of motor and sensory recovery 2 . However, studies have shown 61% of patients with SCI experience debilitating chronic pain that affects mood, functioning, and quality of life 3 . Improving the management of pain is a top priority for these SCI patients over research in other neurological deficits like paraplegia.…”

Section: Introductionmentioning

confidence: 99%

“…Improving the management of pain is a top priority for these SCI patients over research in other neurological deficits like paraplegia. The pain associated with SCI can be divided into nociceptive pain, neuropathic pain (NP), other pain, or unknown pain 3 . Nociceptive pain arises from musculoskeletal structures and viscera, while NP can be due to incorrect transmission because of the spinal cord and nerve damage 4 …”

Section: Introductionmentioning

confidence: 99%

“…Presently, no treatment has been effective for the management of NP in SCI. Gabapentin and pregabalin are two anticonvulsant medications that have been transitioned to use for SCI pain and are first‐line treatment for NP following SCI 3 . Further, antidepressants and opiates are also used 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Gabapentin and pregabalin are two anticonvulsant medications that have been transitioned to use for SCI pain and are first‐line treatment for NP following SCI 3 . Further, antidepressants and opiates are also used 3 . Unfortunately, these pharmacological treatments are only partly successful in relieving pain and many patients discontinue these medications due to unwanted side effects that include dry mouth, spasticity, trembling, dementia, blurred vision, weakness, low back or side pain, and sleep disturbances 3 .…”

Section: Introductionmentioning

confidence: 99%

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The role of the insula in chronic pain following spinal cord injury: A resting‐state fMRI study

Mandloi,

Syed,

Shoraka

et al. 2023

Journal of Neuroimaging

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Background and PurposeSpinal cord injury (SCI) results in the loss of motor and sensory function from disconnections between efferent and afferent pathways. Most SCI patients are affected with chronic neuropathic pain, but there is a paucity of data concerning neuroplastic changes following SCI. Chronic pain disrupts default networks and is associated with abnormal insular connectivity. The posterior insula (PI) is associated with the degree of pain and intensity of pain. The anterior insula (AI) is related to signal changes. Comprehension of SCI pain mechanisms is essential to elucidate effective treatment options.MethodsThis study examines the insular gyri functional connectivity (FC) of seven (five male, two female) SCI participants with moderate‐severe chronic pain compared to 10 (five male, five female) healthy controls (HC). All subjects had 3‐Tesla MRI performed and resting‐state functional MRI (fMRI) was acquired. FC metrics were obtained from the comparisons of resting‐state fMRI among our various groups. A seed‐to‐voxel analysis was pursued, encompassing six gyri of the insula. For multiple comparisons, a correction was applied with a significance level of p < .05.ResultsThere were significant differences in FC of the insula between SCI participants with chronic pain compared with HC. In the SCI participants, there was hyperconnectivity of the AI and PI to the frontal pole. In addition, there was increased FC noted between the PI and the anterior cingulate cortex. Hyperconnectivity was also observed between the AI and the occipital cortex.ConclusionsThese findings illustrate that there is a complex hyperconnectivity and modulation of pain pathways after traumatic SCI.

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Different Gabapentin and Pregabalin Dosages for Perioperative Pain Control in Patients Undergoing Spine Surgery

Tsai,

Hu,

El Sammak

et al. 2023

JAMA Netw Open

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IMPORTANCEPatients undergoing spine surgery often experience severe pain. The optimal dosage of pregabalin and gabapentin for pain control and safety in these patients has not been well established.OBJECTIVETo evaluate the associations of pain, opioid consumption, and adverse events with different dosages of pregabalin and gabapentin in patients undergoing spine surgery.DATA SOURCESPubMed/MEDLINE, Embase, Web of Science, Cochrane library, and Scopus databases were searched for articles until August 7, 2021.STUDY SELECTIONRandomized clinical trials conducted among patients who received pregabalin or gabapentin while undergoing spine surgery were included.DATA EXTRACTION AND SYNTHESISTwo investigators independently performed data extraction following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) reporting guideline. The network meta-analysis was conducted from August 2022 to February 2023 using a random-effects model.MAIN OUTCOMES AND MEASURESThe primary outcome was pain intensity measured using the Visual Analog Scale (VAS), and secondary outcomes included opioid consumption and adverse events.RESULTSTwenty-seven randomized clinical trials with 1861 patients (median age, 45.99 years [range, 20.00-70.00 years]; 759 women [40.8%]) were included in the systematic review and network meta-analysis. Compared with placebo, the VAS pain score was lowest with gabapentin 900 mg per day, followed by gabapentin 1200 mg per day, gabapentin 600 mg per day, gabapentin 300 mg per day, pregabalin 300 mg per day, pregabalin 150 mg per day, and pregabalin 75 mg per day. Additionally, gabapentin 900 mg per day was found to be associated with the lowest opioid consumption among all dosages of gabapentin and pregabalin, with a mean difference of −22.07% (95% CI, −33.22% to −10.92%) for the surface under the cumulative ranking curve compared with placebo. There was no statistically significant difference in adverse events (nausea, vomiting, and dizziness) among all treatments. No substantial inconsistency between direct and indirect evidence was detected for all outcomes.CONCLUSIONS AND RELEVANCEThese findings suggest that gabapentin 900 mg per day before spine surgery is associated with the lowest VAS pain score among all dosages. In addition, no differences in adverse events were noted among all treatments.

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The Efficacy, Adverse Events, and Withdrawal Rates of the Pharmacological Management of Chronic Spinal Cord Injury Pain: A Systematic Review and Meta-Analysis

Cited by 8 publications

References 70 publications

Living Systematic Review on Cannabis and Other Plant-Based Treatments for iii Chronic Pain: 2022 Update

Living Systematic Review on Cannabis and Other Plant-Based Treatments for iii Chronic Pain: 2022 Update

The role of the insula in chronic pain following spinal cord injury: A resting‐state fMRI study

Different Gabapentin and Pregabalin Dosages for Perioperative Pain Control in Patients Undergoing Spine Surgery

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