Out of the 11 studies included in this review, 6 demonstrated analgesic superiority of selective cannabinoids compared to placebo based on change in NRS pain scores,15,16,19–21 or on proportion of patients achieving more than 30% reduction in intensity of pain as compared to baseline scores.18 Meta-analysis of data from the 10 trials that reported pain scores revealed a small reduction of pain scores with selective cannabinoids when compared to placebo or dihydrocodeine in patients with NP (mean difference −0.65 points; 95% CI, −1.06 to −0.23 points; P = .002, I2= 60%) (Table 2, Figure 2).13–16,18–23
Comparison of Different Selective Cannabinoid Types
We examined results for the 3 types of selective cannabinoids evaluated in these trials. Only 1 trial evaluated analgesic potential of dronabinol in patients with central NP and it reported superiority of this selective cannabinoid over placebo.19 Three trials evaluated analgesic efficacy of nabilone in NP.20,21,23 Two of these trials (1 trial enrolled patients with central NP21 and the other trial enrolled patients with peripheral NP20) concluded that use of nabilone was associated with analgesic benefit in NP. The third trial on nabilone enrolled patients with mixed central and peripheral NP and it demonstrated analgesic inferiority of nabilone in comparison to dihydrocodeine.23 Meta-analysis of data from these 3 trials revealed no significant reduction of the 11-point pain NRS with nabilone when compared to placebo or dihydrocodeine in patients with NP (mean difference −1.22 points; 95% CI, −2.79 to 0.36 points; P = .13; I2= 85%) (Figure 3A). Seven trials13–18,22 evaluated analgesic efficacy of nabiximols in NP and 613–17,22 of these reported pain scores. Two of these trials (one for central NP16 and the other for peripheral NP15) reported analgesic superiority of nabiximols over placebo. The other 5 trials did not show analgesic benefit with nabiximols (2 on central NP,13,22 2 on peripheral NP,17,18 and 1 on mixed central and peripheral NP14). Meta-analysis of data from the 6 trials that reported pain scores revealed a significant but clinically small reduction of the 11-point pain NRS with nabiximols when compared to placebo in patients with NP (mean difference −0.50 points; 95% CI, −0.89 to −0.12 points; P = .010, I2= 43%) (Figure 3B).
Efficacy of Selective Cannabinoids in Central and Peripheral Neuropathic Pain
We conducted meta-analyses to see whether the effect of selective cannabinoids differed depending on the location of NP—central, peripheral, and combined central-peripheral (Table 2). Two of 5 studies involving patients with central NP reported significantly lower pain scores in the selective cannabinoid group.16,21 Meta-analyses of the data from the 5 trials on central NP demonstrated significant analgesic benefit with selective cannabinoids (mean difference −0.73 points; 95% CI, −1.26 to −0.20 points; P = .007, I2= 51%) (Figure 4A).13,16,19,21,22
Three of the 4 studies involving patients with peripheral NP reported significantly lower pain scores favoring selective cannabinoids.15,17,18,20 However, meta-analyses of the data from the 3 trials on peripheral NP that involved use of selective cannabinoids and reported pain scores did not demonstrate analgesic benefit (mean difference −0.72 points; 95% CI, −2.04 to 0.59 points; P = 0.28, I2= 75%) (Figure 4B).15,17,20 Two studies of selective cannabinoids in patients with mixed central and peripheral NP did not demonstrate analgesic superiority of selective cannabinoids over the comparators—1 of these trials involved the comparison of nabiximols against placebo14 and the other compared nabilone against dihydrocodeine.23
A variety of domains associated with pain were assessed by trials on selective cannabinoids included in this review (Table 2). Five of the 8 studies13,19,20,22,23 that assessed QoL demonstrated an improvement in this parameter with selective cannabinoids (questionnaires used to assess QoL included Short Form-36,14,17,19,23 European Quality of Life—5 Domains index score,17,18,20 and General Health Questionnaire –1222). Only one15 of the 3 studies that assessed physical function15,19,22 reported an improvement in this domain. Six of the 7 studies that assessed quality of sleep found an improvement in this parameter.13,15,16,18,20,22 Only 116 of the 316,20,23 studies that measured anxiety using validated questionnaires reported an improvement in the Anxiety subscale on psychological function based on the Hospital Anxiety and Depression Scale. Five of the 6 studies that included satisfaction of participants as 1 of the outcomes reported positive results for this parameter.15,16,18,20,21 Three of the 4 studies demonstrated improvement in QST profile (rise in thresholds) of the participants with selective cannabinoids.15,18,19
All 11 studies included in this review collected data on adverse effects with selective cannabinoids and study medications. The majority of reported adverse effects with selective cannabinoids were mild to moderate. The most common adverse effects with selective cannabinoids were dizziness/lightheadedness, somnolence, and dry mouth. Adverse effects usually occurred at the onset of treatment and subsided over time, indicating development of tolerance (Table 2).
We also assessed reports of severe adverse effects requiring withdrawal from the trials. These included confusion in 2 patients20 and headaches in 1 patient on nabilone.21 In a study with a crossover design, 4 participants (out of 96) on nabilone withdrew from the trial due to intolerance whereas 8 participants on dihydrocodeine ceased taking this medication.23 Two patients developed severe adverse events from selective cannabinoids (agitation and paranoid ideation).16 In another study, 11 (18%) patients withdrew from the nabiximols group because of adverse effects compared to 2 (3%) in the placebo group.15 All other studies demonstrated similar patient withdrawal rates between the trial arms.
There did not appear to be a correlation between the maximum dose (48 sprays per day) allowed for nabiximols and incidence or severity of adverse effects because the dose range utilized per 24 hours by participants in studies on nabiximols was fairly low (4–11 sprays).
For the primary outcome, the I2 statistic was 60% for the meta-analysis of pain NRS from all selective cannabinoid RCTs, it was 85% for comparison of mean postintervention pain scores for trials on nabilone, and 43% for comparison of mean postintervention pain scores for trials on nabiximols. These results indicate moderate-to-high heterogeneity. Several characteristics of these studies may have contributed to heterogeneity in our review including types of patient populations, timing of assessing primary outcome, and variations in dose. To explore heterogeneity, we conducted subgroups using meta-regression and a sensitivity analysis and found no significant difference based on central versus peripheral and on risk of bias.
We performed meta-regression analysis to assess whether there was a significant interaction between location of pain (central versus peripheral) and treatment effects of selective cannabinoids. We found no significant difference in effect size between studies on selective cannabinoids that enrolled participants with central pain compared to studies that enrolled participants with peripheral pain (P = .998 and .958 when assessed using normal and non-normal distribution assumptions, respectively).
We performed a sensitivity analysis by removing the 1 trial with a high risk of bias.17 This trial also reported a significant effect of depression on NP scores with patients in both arms who had more depression also had a more pronounced response to the study treatments. Meta-analysis of data from the other 9 trials on selective cannabinoids that had a low risk of bias (ie, after excluding 1 trial with a high risk of bias17) showed that the significant but clinically small reduction in pain NRS in patients with NP remained (−0.70 points; 95% CI, −1.10 to −0.31 points; P = .0005, I2= 57%) (Supplemental Digital Content 3, Figure 1, http://links.lww.com/AA/B749).13–16,19–23
We also evaluated probability of publication bias in trials on selective cannabinoids for NP. The funnel plot (Supplemental Digital Content 4, Figure 2, http://links.lww.com/AA/B750) was asymmetrical suggesting the possibility of publication bias. Although other causes including clinical heterogeneity could be responsible for this finding, we decided to perform Begg’s and Egger tests for publication bias but the P values for publication bias were nonsignificant (P = .371 and .103, respectively). This suggests that there was no publication bias. It is also important to acknowledge that there were only 10 studies in our meta-analysis and 10 is the minimum recommended number of studies for constructing a funnel plot.25,26
Based on the quality of the evidence included in this review and the strength of effect, it can be recommended that selective cannabinoids may be used as adjunct analgesics in patients with NP syndromes (GRADE: weak recommendation; moderate quality evidence) (Supplemental Digital Content 5, Table 3, http://links.lww.com/AA/B751). Selective cannabinoids may be associated with improvement in QoL, sleep, patients’ reports of impression of positive change, and improved sensory and pain thresholds with psychometric testing. The overall small analgesic benefit and the associated adverse effects associated with use of selective cannabinoids should be discussed with patients and their preferences and values considered before prescribing selective cannabinoids. Further research in this field is justified because there is a lack of information about appropriate dosages and duration of treatment, impact of these medications on physical and psychologic functioning, and adverse effects.
This is the first SR-MA of RCTs that focuses on the analgesic efficacy of selective cannabinoids when used as adjuncts in relieving refractory central and peripheral NP of moderate-to-severe intensity. It reveals that daily doses of 2.5 to 10 mg of dronabinol, 1 to 4 mg of nabilone, and 8.3 sprays of nabiximols when administered over 2 to 15 weeks are associated with analgesic benefit compared to placebo at 2 weeks or more after initiation of treatment. The reduction in mean NRS pain scores (0–10 scale) in patients receiving selective cannabinoids compared to placebo is significant but clinically small. The quality of evidence is moderate and the strength of recommendation is weak for analgesic efficacy of selective cannabinoids in this clinical setting. Among the different selective cannabinoids, use of nabiximols and dronabinol, but not nabilone, conferred an analgesic benefit. Evaluation of subgroup results of analgesic impact of selective cannabinoids on different locations of NP (central versus peripheral) did not reveal a significant difference. For secondary outcomes, use of selective cannabinoids was associated with improvements in QoL and sleep, and enhanced patient satisfaction but the impact on physical and psychologic function was unclear. Serious adverse effects were rare with the doses of selective cannabinoids used in these trials.
The role of selective cannabinoids in relieving chronic pain has been evaluated in a few narrative reviews over the last few years but no SR-MAs on their role in NP have been reported.10,11,27–29 Conclusions of these reviews vary with 1 review suggesting that selective cannabinoids have equianalgesic effect to codeine and are associated with unwanted side effects,27 whereas a meta-analysis of trials on selective cannabinoids for MS-related pain revealed significant pain relief compared to placebo.28 Other recent systematic reviews on heterogeneous pain populations (in terms of etiologies and presentations) demonstrated analgesic superiority of selective cannabinoids and cannabis in 2 reviews11,29 or were inconclusive.10 Selective cannabinoids and cannabis preparations used in trials included in these reviews varied in formulation (eg, smoked cannabis, vaporized cannabis, fatty acid amide hydrolase inhibitors, oral mucosal sprays, and oral cannabis extracts) making it difficult to understand and establish whether there was a dose-response relationship. Our SR-MA is clinically relevant because it is the first synthesis of published data to exclusively focus on recent trials on chronic NP that involved use of selective, prescription cannabinoids.
Population Included in This Review
There was a moderate degree of clinical and statistical (60%) heterogeneity among the trials included in this SR-MA. We included trials on selective cannabinoids for patients with central NP pain because this type of pain can be extremely challenging to relieve. NP was assessed using accepted methods (clinical assessment in all studies and use of validated questionnaires for NP or QST in 1 study). However, current ability to reliably diagnose central NP is uncertain.30 One of the trials on central NP included in our SR-MA included only patients with sensory abnormalities at the maximal pain site but patients with multiple sclerosis can also have spasm-related pain.19 Spasm-related pain has been considered as nonneuropathic by some investigators.19
Efficacy of Selective Cannabinoids in Relieving Neuropathic Pain
A self-titration dosing schedule was chosen by investigators of trials on nabiximols (THC-CBD sprays) included in our SR-MA because there is high intersubject variability in the bioavailability of nabiximols.13–18,22 The recommended dose range is between 1 and 48 sprays per day but the mean daily dose used by participants included in this SR-MA was 8.3 sprays.31 This suggests that only a few patients will progress to the upper limit of the allowed dose range. Self-titration also enables patients to achieve their individual optimum therapeutic dose by balancing analgesia against adverse effects and allowing variation of dose depending on the levels of pain and activity. However, allowing wide dose ranges makes it difficult to ascertain presence or absence of a dose-response effect. It should also be acknowledged that although the therapeutic effects of cannabis have often been attributed to THC, the second major constituent of the trial medication—CBD has been shown to have effects, which may be additive to those of THC in pain relief in animal models, and CBD also has the potential to ameliorate some of the psychoactive effects of THC.32
Nabilone is a selective cannabinoid that is administered through the oral route. Some authors have also questioned the appropriateness of trials of selective cannabinoids using oral administration due to the variability in their gastrointestinal absorption and crossover designs because of their long half-lives.27 The recommended daily therapeutic dose of nabilone varies from 1 to 4 mg. Of the 3 trials on nabilone included in our SR-MA, the 2 trials that reported analgesic benefit with nabilone allowed flexible dosing of nabilone (1–4 mg per day),20 or a fixed daily dose of nabilone of 2 mg,21 but another trial that also allowed a fixed daily dose of 2 mg did not report any analgesic benefit.23 We conclude that it is not possible to define a specific dose of nabilone that is associated with an analgesic response in patients with NP and gradual escalation of dose titrated to analgesic benefit is recommended.
Magnitude of Analgesic Effect and Probability of Treatment Success With Selective Cannabinoids
Our SR-MA found that selective cannabinoids were associated with a significant but small analgesic benefit of change (reduction) in pain by −0.65 points (95% CI, −1.06 to −0.23 points; P = .002) on an 11-point NRS for pain. However, patients enrolled in the trials included in our SR-MA had moderate-to-severe refractory NP despite the use of recommended therapies.8,9 It is recognized that treatment of NP, and in particular syndromes caused by central nervous system lesions, is difficult and randomized trials evaluating treatments of central pain are limited.33 The pain reduction seen in this study is comparable to the effect of other drugs used in the treatment of NP conditions.34 A meta-analysis of more than 2700 patients with various painful conditions suggested approximately a 30% or a reduction by 2 points in the 11-point NRS for pain as being clinically significant but it notably did not include patients with NP, in which “relatively small decreases in pain intensity are often highly valued by the patients.”35 One trial included in our SR-MA reported that the numbers needed to treat to achieve a 50% reduction in central pain in at least 1 patient was 3.7 (95% CI, 2.2–13.0),16 similar to that obtained in the trial on dronabinol that was also included in our SR-MA (3.5; 95% CI, 1.9–24.8).16,19 It is important to recognize that these numbers needed to treat are significantly lower (ie, better) compared to those for some first-line medications for treatment of NP.9
Central Versus Peripheral Neuropathic Pain
Meta-analysis of data on analgesic impact of selective cannabinoids on central and peripheral NP suggested a small analgesic benefit in patients with central NP only but meta-regression analysis revealed that the location of pain did not influence analgesic efficacy of selective cannabinoids. The pathologic mechanisms of NP in these 2 locations may be different with sensitization in spinal cord and brain playing a more important role in central NP. Pain associated with brachial plexus injury and multiple sclerosis, although considered to be central, can have different phenotypes (related to spasms, plaques in the central nervous system, and musculoskeletal pain).22 These factors may explain the reason for 1 of the trials in our SR-MA that found a lack of analgesic benefit with nabilone over dihydrocodeine in a population with central and peripheral NP syndromes secondary to a variety of etiologies.23
Impact of Coanalgesic Therapy
All trials included in this SR-MA except 1 allowed continuation of existing analgesic regimes.19 Depriving a patient of therapies for NP during a placebo-controlled trial is debatable. Clinical practice is moving toward combination therapies due to the realization that multiple mechanisms play a role in chronic NP.36 Experimental studies have also shown that THC may not be an effective analgesic when used alone but it displays a pronounced synergistic effect when used with an opioid.37 Cannabis may also have synergistic effects with opioids with a recent publication suggesting that cannabis may be effective in weaning patients with chronic postsurgical pain from high-dose opioids.38
Impact of Selective Cannabinoids on Nonanalgesic Domains of Neuropathic Pain
Five13,19,20,22,23 of the 7 trials13,14,17,19,20,22,23 included in this review demonstrated a positive effect on QoL despite a relatively short duration of treatment in most of the studies while 120 of 3 studies16,20,23 on psychologic function reported an improvement in the Anxiety subscale of Hospital Anxiety and Depression Scale. It is possible that the measures used to detect changes in mood were not adequately sensitive to detect milder degrees of psychologic impairment because potential participants who had significant psychologic morbidities were excluded from the trials. Alternatively, the paradoxical effects of THC, or the ability of CBD to block some of the psychomimetic effects of THC, may explain the lack of change in mood. Assessment of mood is important in any trial involving use of selective cannabinoids because of their known anxiolytic action,39,40 while there are also concerns about the ability of selective cannabinoids to induce psychosis and schizophrenia.41
Six13,15,16,18,20,22 of the 7 studies13,15,16,18,20,22,23 included in our SR-MA reported better quality of sleep with selective cannabinoids while 515,16,18,20,21 out of the 6 studies13,15,16,18,20,21 that included assessment of patient satisfaction or global impression of change reported positive results. This finding, despite a lack of corresponding significant change in mood, suggests that patients felt a benefit from reduction in pain, improvement in quality of sleep, or both.16
Cannabis for Neuropathic Pain
To ensure comprehensiveness of our efforts to evaluate role of selective cannabinoids in NP, we also reviewed the evidence for cannabis (smoked or vaporized medical marijuana) in relieving NP. We found 6 RCTs that evaluated smoked or vaporized marijuana of various strengths against placebos for treatment of NP (Supplemental Digital Content 6, Table 4, http://links.lww.com/AA/B752 and Supplemental Digital Content 7, Table 5, http://links.lww.com/AA/B753).42–47 Two studies enrolled patients with HIV NP,42,43 1 study included patients with posttraumatic NP,45 1 study included patients with diabetic neuropathy,44 and another 2 studies enrolled patients with NP syndromes secondary to a variety of etiologies (complex regional pain syndrome type I, thalamic stroke, spinal cord injury, peripheral neuropathy, radiculopathy, or trauma).46,47 Four studies examined peripheral NP42–45 and 2 studies examined a mix of central and peripheral NP.46,47 Crossover trial design was used for all 6 studies except 1.42 All studies had similar participant inclusion criteria as studies on selective cannabinoids included in our SR-MA.
Overall bias was low in these 6 studies on cannabis (Supplemental Digital Content 8, Table 6, http://www.links.lww.com/AA/B754). Interventions in all 6 studies were of short duration (up to 5 days). Dose of THC per day ranged from 1.875 to 34 mg.44,48 Similar to the RCTs on selective cannabinoids included in our SR-MA, cannabis preparations were used as an adjunctive medication in the 5 studies. All studies demonstrated significant pain reduction with cannabis compared to placebo. Diversity in methodology and reporting of pain intensity ruled out the prospect of performing a meta-analysis. Similar to selective cannabinoids, escalation in strength of THC for cannabis has not clearly been demonstrated to provide superior analgesia and result in worsened neuropsychologic performance.46
Secondary outcomes for improvement in anxiety and depression/mood were reported with cannabis in 243,45 of 343,45,46 studies. One study also reported improvement in sleep.45 QST testing was performed in 3 studies and there was no evidence of change in thresholds toward normal in any of these studies.42,46,47 Two studies reported higher participant satisfaction with cannabis.46,47 Finally, almost all adverse events relating to the interventions were considered mild to moderate. Adverse effects were similar to effects with selective cannabinoids, and only 1 study reported that a single participant withdrew due to psychosis.43 Detailed results for 5 out of 6 of these RCTs have been recently published in a narrative review.48
Adverse Effects of Selective Cannabinoids
It is unclear whether use of selective cannabinoids is associated with significant adverse effects. Data on this aspect may be affected by the type of selective cannabinoid, its dose, and the comparator used in a trial. A review of 31 studies on adverse effects of medical cannabinoids revealed an increase in nonserious adverse events when compared to placebo.49 However, 1 trial included in our SR-MA reported that the number of patients with adverse events decreased during active treatment.19 This observation may be due to increasing tolerance to the drug over time but 17% of the patients were not able to tolerate the maximum allowed dose of dronabinol19 or other selective cannabinoids. This observation also suggests that adverse effects may prevent attainment of therapeutic levels of selective cannabinoids.
Long-term safety data in use of selective cannabinoids and cannabis for NP are limited. A recent long-term safety review of nabilone use for posttraumatic stress disorder patients cited 2 of our included studies (limited by a trial duration of only 9 weeks)20,21 and highlighted similar adverse effects.50 Data from an open-label follow-up for 1 year of 104 patients with multiple sclerosis who were taking nabiximols (mean of 6.2 sprays/day) for spasticity reported predominantly gastrointestinal adverse effects. Twenty-one of 22 reported adverse effects were considered nonserious, while 1 was serious due to fall resulting in fracture.51 A 1-year safety study on cannabis (average 2.5 g/d) with 12.5% THC for pain reported an increased risk of nonserious adverse events and risk of chronic bronchitis.52
Recreational use of cannabis suggests that it has some potential for dependence.53 Heavy, regular recreational cannabis smoking at a young age in vulnerable subjects may also be associated with an increased risk of subsequently developing schizophrenia.54 It is also believed that mental illness may be aggravated by cannabis. For this reason, patients with a history of significant psychiatric illness were excluded from trials included in this SR-MA. This limits the generalizability of results of these trials and of this SR-MA because patients with significant levels of pain often have coexisting mood disorders.
Limitations of Current Evidence
Despite our rigorous attempts to identify all current evidence, there remain several unanswered questions regarding efficacy of selective cannabinoids in patients with NP. We are unable to comment on the ideal proportions of THC and CBD in nabiximols preparations because there is a significant variation in amounts of THC and CBD content used in trials. The dose per administration and daily maximum limits also differed across RCTs in our SR-MA. Furthermore, analgesia was assessed over a wide range of time periods after initiation of study interventions. The diagnosis of NP was primarily clinical and other means of diagnosis including QST and validated questionnaires were not used consistently. Finally, the effect of selective cannabinoids on physical disability, psychological disability, sleep, and on QoL was also not assessed rigorously.
Suggestions for Future Research
Future RCTs conducted with larger enrollment may be able to better quantify the analgesic potential of selective cannabinoids for NP. One particular concern regarding selective cannabinoids is the variability in content, dosing, and route of administration. Analgesic impact and adverse effects of different proportions of THC and CBD should be assessed in trials. It is important to evaluate the efficacy of this intervention in NPs of various etiologies (central and peripheral) that cause moderate-to-severe pain intensities. Diagnosis needs to be standardized and confirmed through the use of validated NP questionnaires (eg, Douleur Neuropathique 4 questionnaire, Leeds assessment of neuropathic symptoms and signs).
Synthesized data from our SR-MA showed that nabiximols have an analgesic effect, whereas nabilone may not relieve NP. To further understand the analgesic potential of selective cannabinoids, we propose a multicenter RCT on patients with NP with 4 treatment arms: CBD, THC/CBD, nabilone, and placebo. We propose these 4 groups because it may yield further insight in the debate concerning which selective cannabinoid provides greater analgesic effect. The sample size for this trial would be at least 70 patients per group (ie, 280 patients in all) for an expected difference between pain NRS (0–10 scale) means of 1.8 and the within-group SD of 3. This sample size has been determined to give a 90% chance of rejecting the null hypothesis of no difference between means at an α of .0125 and using a Bonferroni adjustment to the size of the test to compensate for multiple comparisons. Pain scores should be measured at multiple time intervals after initiation of intervention: acutely (eg, at 1–2 weeks after initiation of therapy), intermediate (eg, at 1 month), and long-term (eg, at 3, 6, 12 months and beyond). Stratification of patient data based on degree of pain relief would allow for reporting of proportion of significant versus limited responders to the intervention and further isolate patient characteristics that are more responsive to the intervention. Important secondary outcome measurements to include in this proposed trial are as follows: emotional functioning, physical functioning, patient satisfaction with treatment (all assessed using validated questionnaires), and meticulous attempts to identify and record adverse effects. These recommendations are in accordance with the core outcome domains of the IMMPACT guidelines for designing clinical trials to evaluate interventions for chronic pain conditions.55
There was moderate quality evidence to suggest nabiximols is effective in reducing NP. There was no significant difference on the analgesic impact of selective cannabinoids on different locations of NP. Selective cannabinoids may have a role as coanalgesic therapy for refractory NP. Challenges to overcome in subsequent studies include ensuring that trials are blinded (patients, clinical team, data collectors and assessors, data analysts) with standardization of pain diagnosis, length of treatment, assessment of dose-response, homogeneity of patient population, and inclusion of QoL indicators.
Name: Howard Meng, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Name: Bradley Johnston, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Name: Marina Englesakis, MLIS.
Contribution: This author helped in negotiation, development, revision, and running of database search strategies; management of citations; and documentation of searches and search results.
Name: Dwight E. Moulin, MD.
Contribution: This author helped analyze the data and write the manuscript.
Name: Anuj Bhatia, MBBS, MD, FRCPC, FRCA, FFPMRCA, FIPP, EDRA, CIPS.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
This manuscript was handled by: Honorio T. Benzon, MD.
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