Pain in Parkinson’s disease (PD) is a debilitating symptom with a prevalence of 68%, yet is untreated 50% of the time. What is unclear, however, is which treatment is optimal for minimizing pain severity in PD. Thus, the objective of this systematic review and meta-analysis was to investigate the efficacy of a variety of novel, complimentary, and conventional treatments for pain in PD and elucidate which therapy is the most effective. A systematic search was performed using MEDLINE, PsycINFO, Embase, CINAHL, and CENTRAL databases. To identify additional articles, manual searches of reference lists of included trials were also searched. Major neurology conference proceedings occurring between January 2014 and February 2018 were also searched to identify unpublished studies that may be potentially eligible. Twenty-five randomized controlled trials that encompassed medical, surgical, and complementary therapies met our inclusion criteria and exhibited moderate quality evidence. Two reviewers conducted assessments for study eligibility, risk of bias, data extraction, and quality of evidence rating. A conservative random-effects model was used to pool effect estimates of pain severity. The greatest reductions in pain were found with safinamide (Standardized mean difference = –4.83, 95% CI [–5.07 to –4.59], p < 0.0001), followed by cannabinoids and opioids, multidisciplinary team care, catechol-O-methyltransferase inhibitors, and electrical and Chinese therapies. Moderate effects in reducing pain were in pardoprunox and surgery, while the weakest effects were in dopaminergic agonists and miscellaneous therapies. Safinamide is an important adjunct to standard parkinsonian medication for alleviating pain in PD.

Parkinson’s disease (PD) is a progressive neurodegenerative condition with a prevalence of 0.3% of the entire population (or 1% for people above the age of 65), and continues to increase alarmingly with associated economic and social burden [1-3]. PD is often associated with muscle rigidity, tremors, and cognitive decline particularly in patients over 40 years of age. Pain is an extremely common non-motor symptom that is prevalent among 68–95% of PD patients [4-7]. Pain in PD has a significant impact on quality of life, evidenced by its association with higher scores of both depression and anxiety in these patients [8]. Despite the high rates of pain prevalence, between 25 and 50% of PD patients are receiving no treatment for their pain [4-6]. A notable concern in PD is the experience and severity of pain across various patient populations [9].

Pain in PD is attributable to a primary or secondary cause. Primary causes are associated with early morning dystonia or motor fluctuations compared to secondary causes that are associated with musculoskeletal pain [10]. Although various treatments exist for PD, it is unclear as to which is most effective in alleviating pain in PD. We performed a meta-analysis of randomized controlled -trials (RCTs) to determine the effect of conventional, complementary or experimental therapies on pain severity in PD.

The reporting of this study is in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [11], and the protocols for reviews detailed in the Cochrane Handbook for Systematic Reviews of Interventions [12] (Appendix 1).

Identification of Studies

A systematic search was performed using MEDLINE, PsycINFO, Embase, CINAHL, and CENTRAL from the inception of the databases to February 2, 2018. To increase the sensitivity of the search, we used MeSH and EMTREE headings in various combinations and supplemented with free text (Appendix 2). Reference lists of included trials were also searched to identify additional articles. Major neurology conference proceedings occurring between January 2014 and February 2018 were also searched to identify unpublished studies that may be potentially eligible.

Assessment of Eligibility

Two authors independently screened titles and abstracts which were followed by a full-text screening to determine eligibility of clinical trials. All disagreements were resolved through consensus and via arbitration by a senior author.

All studies meeting the following criteria were included:

(1) RCTs only.

(2) Trials assessing a continuous measure of pain severity.

(3) Adult patients (age ≥18) with idiopathic PD.

No restrictions were made for language, publication date, presence of absence of co-interventions, or length of follow-up.

Assessment of Risk of Bias

The risk of bias tool in Review Manager (RevMan) by the Cochrane Collaboration was used by 2 reviewers (A.R.Q. and S.M.) to independently perform a risk of bias assessment [12]. Study authors were contacted to resolve any concerns.

Data Extraction

The extracted data from available studies included first author’s last name, publication year, RCT design, scale used to calculate pain severity, therapeutic intervention, funding source, and country. Furthermore, data for treatment and control groups were extracted in terms of sample size, age, gender, disease duration, and the amount of missing or lost data in terms of participants. In the event where important data was unclear or missing, we attempted to contact study authors to retrieve such information.

Statistical Analyses

Agreement of reviewers’ assessment for study eligibility was calculated using Cohen’s kappa coefficient (κ), with κ ≥0.65 being considered adequate [13]. The intraclass correlation coefficient was used to calculated reviewer agreement for the risk of bias assessment. A conservative random-effects model of DerSimonian and Laird [14] was used to pool effect estimates of pain severity using Prometa 3. Pain severity effect estimates relative to control were generated using the standardized mean difference (SMD) with 95% CIs. Negative values for pain severity represent pain reduction, while positive values represent pain augmentation. Publication bias was examined through funnel plots, as well as Egger’s and Begg’s tests for publication bias. All tests of significance were 2-tailed, with a significance threshold set at p = 0.05.

Evaluation of Heterogeneity

Heterogeneity was quantified using the I2 statistic from the X2 test for heterogeneity. In accordance to the interpretation from the Cochrane Handbook, heterogeneity for I2 values between 30 and 60% may be moderate, 50 and 90% may be substantial, while values between 75 and 100% may be considerable [12]. We hypothesized a priori that heterogeneity may be accounted for by treatment drug dosage, the particular procedure of therapy, and stage of the disease.

Sensitivity Analysis

The main analysis consisted of patients who successfully completed follow-up and were analyzed within the eligible trials. Participants with missing data were not included. To explore the effect of missing data, we conducted an a priori sensitivity analysis that used the participants enrolled as the sample sizes for all eligible trials, assuming that the pain severity scores for treatment and control groups remained the same. Furthermore, a second a priori sensitivity analysis included studies with less than 2 ratings of high-risk bias across any of the categories of the risk of bias assessment.

GRADE Quality Assessment and Summary of Findings

The GRADE quality assessment guidelines were used to analyze the quality of evidence for or against the use of treatments in PD for reducing pain [15]. Although RCTs produce the highest quality of evidence, we conducted a quality assessment, as they are still susceptible to bias, imprecision, inconsistency, and poor methodological construct.

Eligible and Included Studies

Out of 876 potentially eligible articles, 175 were duplicates and the remaining 701 titles and abstracts were screened. Subsequently, 27 full-texts were screened and 24 were ultimately eligible for our review (Fig. 1). One study pooled the results of 2 (RCTs [16]. Thus, 25 RCTs were included with a total of 1,744 patients undergoing a therapeutic intervention and 1,610 patients undergoing a control intervention. Agreement between the reviewers for study eligibility was moderately high (κ = 0.724, 95% CI [0.479–0.969], p < 0.0001) and the agreement for risk of bias assessment was very high (intraclass correlation coefficient = 0.856, 95% CI [0.714–0.927], p < 0.0001).

Study Characteristics

The mean age of study participants was 66 years in the treatment and control groups. The proportion of male patients was 61% in the treatment group and 60% in the control group. Mean disease duration of PD was 7.9 (3.5) years and 7.2 (3.4) years in the treatment and control group respectively (Table 1, please see Appendix 3 for group-wise demographics).

The number of trials for each identifiable therapeutic intervention category was 3 for dopaminergic agonists [17-19], 2 for cannabinoids and opioids [20, 21], 3 for surgical methods [22-24], 4 for electrical or Chinese therapies [25-28], 2 for pardoprunox [29, 30], 2 for safinamide [16], 1 for catechol-O-methyltransferase (COMT) inhibitors [31], 1 for multidisciplinary team care [32], and 7 for miscellaneous therapies. Miscellaneous therapies included hydrotherapy [33, 34], massage therapy [35], gym training [36], mindfulness therapy [37], vibration therapy [38], and power yoga [39] (Table 1, with further intervention details in Appendix 4).

Pain severity was reported in 8 trials using the pain subscale of the Visual Analogue Scale (VAS-P) [17, 24, 26, 27, 29, 30, 33, 35], in 8 using section 39 of the Parkinson’s Disease Questionnaire-39 [16, 22, 23, 31, 32, 36, 37, 39], in 4 using the Likert pain scale [18, 19, 34, 38], in 1 using the King Parkinson’s Disease Pain Scale [21], in 1 using question 1.9 of the Movement Disorders Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS Q1.9) [25], in 1 using the McGill Pain Scale [20], and in 1 trial using the Daily Pain Rating Sheet [28] (Table 1).

Risk of Bias

The risk of bias assessment through RevMan is summarized (Fig. 2). The funnel plot for pain severity was fairly symmetric (Fig. 3), with publication bias being statistically insignificant (Egger: p = 0.776; Begg: p = 0.427).

Pain Severity

The largest effects for pain severity reduction were found in safinamide (SMD = –4.83, p < 0.0001), followed by cannabinoids and opioids (SMD = –2.24, p < 0.0001; I2 = 0.00%, p = 0.363), multidisciplinary team care (SMD = –2.01, p < 0.0001), and COMT inhibitors (SMD = –1.81, p < 0.0001). Thereafter was a large effect from electrical and Chinese therapies with considerable heterogeneity (SMD = –0.98, p = 0.020; I2 = 86.9%, p < 0.0001). Moderate sized effects on pain severity reduction were found for pardoprunox with insignificant heterogeneity (SMD = –0.50, p = 0.001; I2 = 69.0%, p = 0.073), followed by surgery with insignificant heterogeneity (SMD = –0.42, p = 0.011; I2 = 26.6%, p = 0.256). Small effects for pain severity reduction were found for dopaminergic agonists with insignificant heterogeneity (SMD = –0.27, p < 0.0001; I2 = 45.8%, p = 0.158). The smallest effect was found for miscellaneous therapies with considerable heterogeneity (SMD = –0.03, p = 0.947; I2 = 91.6%, p < 0.0001; Fig. 4). In the GRADE quality assessment, pain severity was rated as moderate quality of evidence with respect to the need of more trials needed for certain subgroups to confirm the effect, such as for multidisciplinary team care and COMT inhibitors (Table 2).

Sensitivity Analysis

The first sensitivity analysis attempted to compensate for all missing participant data assuming the pain severity scores in control and treatment groups were the same. A –0.02-unit reduction in pain severity was seen in cannabinoids and opioids (SMD = –2.26 vs. SMD = –2.24), while a +0.02-unit increase in pain severity was seen in pardoprunox (SMD = –0.48 vs. SMD = –0.50). Surgery experienced a –0.01-unit decrease in pain severity (SMD = –0.43 vs. SMD = –0.42). Effect sizes of all other groups did not change (Appendix 5).

To provide a more accurate and precise estimate of effect, a subsequent sensitivity analysis was conducted to exclude studies with high-risk bias concerns. Ten studies qualified for the secondary sensitivity analysis, of which 2 were dopaminergic agonists [17, 19], 1 was part of the cannabinoids and opioids class [21], 3 among the electrical and Chinese therapies [25, 27, 38], and 1 each for miscellaneous therapies [37], pardoprunox [30], safinamide [16], and COMT inhibitors [31]. Cannabinoids and opioids experienced a –0.02-unit reduction in pain severity (SMD = –2.26 vs. SMD = –2.24), electrical and Chinese therapies displayed a –0.13-unit reduction in pain severity (SMD = –1.11 vs. SMD = –0.98), and a –0.12-unit reduction in pain severity was seen for pardoprunox (SMD = –0.62 vs. SMD = –0.50). Miscellaneous therapies experienced a +1.70-unit increase in pain severity (SMD = +1.67 vs. SMD = –0.03). No changes to effect sizes were seen in any of the other groups (Appendix 5).

According to the results, the most efficacious treatment is safinamide (SMD = –4.83), followed by cannabinoids and opioids (SMD = –2.30). Safinamide is a selective, reversible monoamine-oxidase B inhibitor that reduces dopaminergic degradation and reuptake. This may make safinamide suitable for PD treatment during OFF periods, which occur as an end-of-dose worsening of the patient’s response to levodopa [40]. However, it also has non-dopaminergic modes of action, including the state-dependent inhibition of voltage-gated sodium channels in the inactivated state and antiglutamatergic activity. These dopaminergic and non-dopaminergic actions may together account for its pain mitigating effects [16]. Numerous studies have shown that safinamide may be very effective at treating parkinsonian pain and is well tolerated in clinical trials [40-42]. Opioids act on opioid receptors and reduce neurotransmission. Cannabinoids control nociceptive thresholds via cannabinoid receptor agonism and may also affect tissues outside the nervous system. Both possess analgesic properties [43].

Multidisciplinary team care (SMD = –2.01), COMT inhibitors (SMD = –1.81), and electrical and Chinese therapies (SMD = –0.98) were the next most effective. The COMT inhibitor trial pertained to entacapone, which inhibits the degradation of levodopa in the peripheral nervous system. Entacapone may therefore be effective in patients with musculoskeletal pain due to motor fluctuations or rigidity [44]. A multidisciplinary team intervention offers a comprehensive approach that may address numerous patient concerns in addition to pain, though it is unclear as to which parts of the team are the most important.

Miscellaneous therapies (SMD = –0.03), dopaminergic agonists (SMD = –0.27), surgery (SMD = –0.42), and pardoprunox (SMD = –0.48) were the least effective. “Miscellaneous therapies” is an umbrella term for a grouping of therapies that lack robust, evidence-based support for their efficacy. Interestingly, mindfulness therapy, gym training, massage therapy and hydrotherapy led to greater pain severity in treated participants compared to controls. This may have been attributable to poor methodological designs such as small sample size, or due to intervention-based exercise. Pardoprunox and other dopaminergic medications were not found to be very effective in reducing pain. This may suggest that pain in PD might not be explained solely by levels of dopamine. Our findings are supported by data from Buhmann et al. [4], who found that analgesics (including opioids) and rehabilitation (a multidisciplinary treatment) were highly effective at treating pain in PD, while dopaminergic medications (unspecified which ones) were comparatively less effective.

There are several limitations in our study. There was considerable heterogeneity in the trials included for Chinese and electrical therapies (I2 = 86.9%), as well as for miscellaneous therapies (I2 = 91.6%). In addition, some studies had significant loss-to-follow up rates, which may result in attrition bias. However, our first sensitivity analysis, which compensated for missing participant data (n = 511), found that effect sizes changed slightly or not at all, suggesting that attrition bias is unlikely to have changed our conclusions. Furthermore, some studies had ineffective blinding, small sample sizes, and notable methodological concerns such as the use of non-validated scales for pain measurement. However, our second sensitivity analysis, which accounted for bias-compromised studies, found that effect sizes were largely unchanged. There were only a few exceptions in studies with weak efficacy, including a substantial increase in the miscellaneous therapies by a single mindfulness therapy study (SMD = +1.67 vs. SMD = –0.03). Studies with large effect sizes in pain severity did not experience changes in effect size, and hence our primary conclusions did not change. A notable limitation was that multiple subgroups such as multidisciplinary team care and COMT inhibitors were each composed of a single trial. Other subgroups such as cannabinoids and opioids, and surgery, or electrical and Chinese therapies had only 2, 3, or 4 studies, respectively. As our search was exhaustive, there is a clear paucity of RCT evidence relating to the aforementioned groups that included a measure of pain severity. Considering the Cochrane Collaboration recommends a minimum number of 10 studies in each subgroup for a subgroup effect to be considered believable [12], our results should be generalized cautiously.

Implications for Clinical Practice and Research

Our findings show that safinamide is an important adjunct to the standard parkinsonian medications for alleviating pain in PD. Analgesics in the form of opioids and cannabinoids were shown to be effective but not nearly to the same extent. Thus, they are an important consideration if a patient responds poorly to safinamide. Although analgesic therapy is effective, only one-half of PD patients with pain report having used them [5, 45]. Nègre-Pagès et al. [45] found that analgesic use was lower for patients with PD pain as opposed to non-PD pain despite greater indices of pain severity and impairment of health-related quality of life. This may have arisen from the fact that PD pain was reported less frequently and/or because dopaminergic drug adjustment may have been preferred for PD pain treatment instead of analgesics. In light of our findings, it appears that dopaminergic drug adjustment yields little benefit, whereas adjusting levels of levodopa via entacapone (or presumably any other drug that inhibits peripheral metabolism of levodopa) may be a more favorable strategy. A multidisciplinary team approach is also recommended; however, additional studies with different team compositions need to be conducted to determine which teams work best. Furthermore, more trials of high methodological quality focusing on different aspects of pain (i.e., severity, temporality, localization, etc.) as well as the pathophysiological mechanisms of pain in PD are needed to form a consensus on the effectiveness of these therapies on patient-important outcomes related to pain.

This systematic review and meta-analysis found that safinamide was the most efficacious among all studied therapies in reducing pain in PD. Cannabinoids and opioids, multidisciplinary team care, COMT inhibitors, and electrical and Chinese therapies all exhibited relatively lower, yet strong efficacy. Pardoprunox, surgery, and dopaminergic agonists had limited efficacy. Complementary therapies have little to no efficacy or increase rather than reduce pain in PD. More trials of high methodological quality focusing on different types of pain, as well as exploring novel therapies for pain in PD are warranted.

The authors report no conflicts of interest. The authors received no funding of any form, or from any funding body for this manuscript.

PRISMA Checklist

Search strategy. Conducted February 25, 2018.

Group-wise summary of demographical characteristics*.

Details of therapeutic intervention and control groups with standardized mean difference (d) and 95% confidence intervals for pain severity in the included trials.

Sensitivity analysis of missing data and lower biased studies for the outcome of pain severity.

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