Efficacy and safety of drug combinations for chronic pelvic pain: a systematic review

The review protocol was registered in the International Prospective Register of Systematic Reviews (PROPSERO) database (CRD42020192231) and previously published. 20 We conducted a systematic review and meta-analysis in accordance with recommendations specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the PRISMA Harms Checklist. 33 We conducted a detailed search on MEDLINE and EMBASE and CENTRAL, from their inception until December 2024. The search included terms related to chronic pelvic pain. The search strategies were developed in consultation with Sandra Halliday, a review coauthor and librarian with expertise in literature searches. The search strategy for EMBASE is shown in Appendix 1, http://links.lww.com/PR9/A319 . We also reviewed the bibliographies of any studies identified for relevance. Two trained reviewers (M.M. and R.P.) independently evaluated studies for eligibility. Screening was performed on titles and abstracts using Covidence software. Citations were stored in EndNote software. Full-text screening was performed on citations eligible for inclusion. Disagreements between reviewers were resolved by discussion and consensus, and if needed, a third reviewer (I.G.) was consulted. Data from included studies were extracted using standardized forms designed uniquely for this review. The forms facilitated extracting information about the chronic pain condition treated, pharmacological interventions and placebo, total numbers of participants, patient inclusion and exclusion criteria, patient characteristics, primary and secondary outcome measurements, along with other study characteristics. This review included double-blind, randomized, controlled clinical trials (RCTs) of combination drug therapies in the treatment of CPP with an outcome measure of pain intensity or pain relief, assessed by a validated measurement tool. Included trials compared combinations of 2 or more different drugs to at least one of the combination's single agent components for the treatment of CPP. Randomized controlled clinical trials with less than 10 participants were excluded to minimize study bias. Only English-language studies were included. 20 The primary outcome of this review was reduction in pain intensity or pain relief, assessed by a validated measurement tool. Secondary outcomes included adverse events, serious adverse events, sexual dysfunction, health-related quality of life, depression and anxiety, and urinary symptoms. Given that there was significant heterogeneity in the studies, a descriptive approach was used to report the primary and secondary outcomes. Risk of bias for each study was independently assessed by 2 reviewers (M.M. and R.P.). We utilized the PRISMA Risk-of-bias tool. Disagreements between reviewers were resolved with discussion and consensus. If necessary, a third reviewer (I.G.) was consulted.

Our systematic search yielded 11,212 results, with 9,866 unique articles remaining after duplicate removal. After 9,833 exclusions at the title and abstract screening stage, there were 33 citations remaining that underwent full-text screening for possible inclusion. A list of studies excluded at the full-text screening stage with associated reasons for exclusion can be found in Appendix 2, http://links.lww.com/PR9/A319 . After group consensus, a total of 8 studies were included in the systematic review. Figure 1 depicts the PRISMA flow diagram. PRISMA flow diagram. Characteristics of the included studies, including patient demographics, interventions, and primary outcomes, are presented in Tables 1 and 2 . The studies included 1,299 participants in total. The average age of patient populations ranged from 29 to 57. The included studies analyzed patients from different pain conditions, including CP/CPPS, chronic pelvic pain from endometriosis, chronic pelvic pain from hemorrhoids, and IC/BPS but did not include primary dysmenorrhea. Treatment duration ranged from 7 days to 24 months. Interventions included drugs from a variety of pharmacological classes, such as alpha-blockers, antibiotics, and hemostatic agents. Method of administration included oral, intramuscular, intravesical, and perineural. Characteristics of included studies. CP/CPPS, chronic prostatitis/chronic pelvic pain syndrome; CPPS, chronic pelvic pain syndrome; NAC, N-acetylcysteine; OCP, oral contraceptive pill; PPS, pentosan polysulphate. Patient demographics in included studies. NAC, N-acetylcysteine; OCP, oral contraceptive pill; PPS, pentosan polysulphate. Results of risk of bias analysis for each individual risk of bias domain are presented in Figure 2 . A risk of bias summary for included studies is presented in Figure 3 . Five were considered low risk, 1 , 2 , 18 , 20 , 25 3 moderate risk, 28 , 31 and 1 unclear risk. 23 Seven of the 9 studies reported the number of patient withdrawals. There were 124 withdrawals across all studies overall. Across all studies, the most common reasons for withdrawal included patient choice, lost to follow-up, and minor adverse events. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies. Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Eight included studies reported on pain intensities and 1 study reported pain intensity reductions; however, given the heterogeneity of studies with respect to pain condition and pharmacologic intervention, a meta-analysis was not able to be conducted. A descriptive summary of the 9 included studies is provided below. Data for pain intensities at baseline and postintervention for all studies are listed in Table 3 . Data on pain intensities from included studies. NAC, N-acetylcysteine; NIH-CPSI, National Institutes of Health-Chronic Prostatitis Symptom Index; NS, normal saline; OCP, oral contraceptive pill; PPS, pentosan polysulphate; SSL, sacrospinous ligament; VAS, visual analogue scale. Alexander et al. 1 evaluated the efficacy of a combination of ciprofloxacin and tamsulosin (antibiotic and alpha-1 antagonist respectively), compared to either component alone in patients with CP/CPPS, administering 50 mg of ciprofloxacin twice daily and 0.4 mg of tamsulosin daily over 6 weeks. A total of 196 patients were included, with NIH-CPSI pain scores evaluated at the end of treatment. Baseline NIH-CPSI pain scores ranged from 11.3 to 12.2 across all groups, and there was a mean reduction in pain scores ranging from −3.0 to −1.6, with no statistically significant differences between groups. Squadrito et al. 28 evaluated the efficacy of a combination of troxerutin and carbazochrome (hemostatic agents) and compared to carbazochrome alone in patients with chronic pelvic pain from hemorrhoids. They administered 150 mg of troxerutin and 1500 mg of carbazochrome intramuscularly, twice daily for a 7-day period. A total of 100 patients were included. Anal discomfort, spontaneous pain, pain with defecation, and proctorrhagia were all found to be significantly reduced from baseline in the combination group, whereas only anal pain and discomfort were significantly reduced from baseline in the monotherapy group. No numerical values or direct statistical comparisons between combination and monotherapy arms were reported. Ozkidik 23 evaluated the efficacy of a combination of hyaluronic acid and chondroitin sulphate (glycosaminoglycans) and compared to the individual components alone in patients with bladder pain syndrome. Patients received 60 mg of hyaluronic acid and 40 mg of chondroitin sulphate via intravesical route once a week for 6 weeks, twice a month for 6 weeks, and then once a month for 24 months. The monotherapy group received either 120 mg of hyaluronic acid or 80 mg of chondroitin sulphate in the same route and frequency. A total of 72 patients were enrolled into the study, and pain scores were measured using the visual analogue scale (VAS). The VAS scores at baseline (SD) for the combination group, hyaluronic acid group, and chondroitin sulphate group were 8.9 (0.5), 8.8 (0.7), and 8.9 (0.6). At the end of the 24-month follow-up period, the scores for the 3 groups were 6.3 (0.6), 7.6 (0.5), and 7.7 (0.6). There was no significant difference between the groups ( P = 0.12). Davis et al. 10 studied the efficacy of a combination intravesical and oral pentosan polysulfate sodium (PPS) (low molecular weight heparins) compared to oral PPS alone in patients with interstitial cystitis. Forty patients were randomized, and patients in the combination group received 200 mg of PPS via intravesical route twice a week for 6 weeks, and 200 mg of oral PPS twice a day for the entire 18 weeks of the study. Patients in the monotherapy group received saline via intravesical route in the same frequency as the combination group and were given 200 mg of PPS twice daily for the 18 weeks of the study. Pain scores on a scale of 1 to 9 were collected at baseline, and follow-up took place at 6, 12, and 18 weeks after enrollment. Baseline mean (25th percentile, 75th percentile) pain scores were the combination and monotherapy groups were 4 (4, 5) and 4.7 (4, 5.8), respectively. The change in scores for the combination group at 6-, 12- and 18-week follow-up were [−1] (0, −2), [−2] (−0.5, −3), [−2] (−1, −3), respectively. The change in scores for the placebo group at the same time points were [−1.5] (−0.5, −3), [−1.5] (0, −3), [−2] (0, −3), respectively. Although there was a significant difference within each group at each of the follow-up time points compared to baseline, there was no significant difference between the combination and monotherapy group in reducing pain associated with interstitial cystitis. Donnez et al. 11 conducted a double-blind randomized trial to study the efficacy of (1) a combination of the oral nonpeptide GnRH antagonist, linzagolix (200 mg), with “add-back” therapy (ABT) involving estradiol and norethindrone acetate compared to (2) a lower dose of linzagolix alone (75 mg) and (3) placebo (n = 162 per arm). At 3 months, the proportion of responders for dysmenorrhea in the 200 mg linzagolix + ABT arm was 72.9% compared with 23.5% in the placebo group ( P < 0.001), while the rates of responders for nonmenstrual pelvic pain were 47.3% and 30.9% ( P = 0.007), respectively. The linzagolix monotherapy arm did not separate from placebo, but it should be noted that this was at a lower dose than in the combination arm. Asgari et al. 2 investigated the efficacy of a combination of N-acetylcysteine (NAC) and oral contraceptives (OCP) compared to OCPs alone in treating chronic pelvic pain associated with endometriosis after laparoscopic surgery. A total of 100 women were randomized to receive either 600 mg of NAC 3 times a day, for 3 consecutive days a week for 3 months and 30 μg ethinyl estradiol and 0.15 mg levonorgestrel (OCP) daily for 6 months. Pain was measured through VAS scores taken at baseline, and then at 3- and 6-month follow-up. The baseline mean VAS scores (SD) for the combination group and for the monotherapy group were 6.70 (2.64) and 7.32 (1.64). The mean VAS scores for the combination group at 3- and 6-month follow-up were 0.43 (1.2) and 0.91 (1.60). The mean VAS scores for the monotherapy group at 3- and 6-month follow-up were 0.61 (1.15) and 1.44 (1.80). Within each group, the mean VAS scores decreased significantly from baseline to the follow-up period ( P < 0.001). However, no significant difference was observed between the combination group and monotherapy group at 3-month ( P = 0.17) or 6-month ( P = 0.106) follow-up. Labat et al. 16 studied the efficacy of adding steroids to lidocaine (local anesthetic) for a pudendal nerve block in patients suffering from pudendal neuralgia. A total of 201 patients were enrolled into the study and received 2 injections as part of the block: sacrospinous ligament and Alcock's canal. Only 1 block was administered for the 90-day period. The first group was randomized to receive 40 mg of lidocaine, 20 mg methylprednisolone, and 30 mL of normal saline (to assess for effects of volume on block efficacy). The second group received 40 mg of lidocaine and 20 mg methylprednisolone for each injection, while the third group received only 40 mg of lidocaine for each injection. Pain was assessed using VAS scores collected at baseline, and at 90-day follow-up. Baseline VAS scores (SD) for the 3 groups were 63.11 (15.86), 63.00 (14.79), and 63.33 (17.87), respectively. For the lidocaine + steroid + saline group, VAS scores at follow-up were 55.37 (25.78), and the mean difference in score was 7.53 (19.85). For the lidocaine + steroid group, VAS scores at follow-up were 54.20 (23.91), and the difference in VAS score was 8.98 (19.74). For the monotherapy group with only lidocaine, mean VAS scores at follow-up were 57.74 (29.28), and the mean difference in VAS scores was 4.56 (19.93). There were no significant differences among any groups when comparing VAS scores at baseline and at 90-day follow-up. Ziaee et al. 31 studied the efficacy of the combination of allopurinol to ofloxacin (xanthine oxidase inhibitor and quinolone antibiotic respectively) compared to ofloxacin alone in men with CP/CPPS. A total of 56 patients were enrolled in the study and randomized to either receive 100 mg of allopurinol and ofloxacin 200 mg (both 3 times daily) for 3 months, or 200 mg of ofloxacin alone for 3 months. Pain was measured using the NIH-CPSI scale at baseline and at 1-, 2-, and 3-month follow-up. Baseline NIH-CPSI pain scores (SD) for the combination and monotherapy group were 12.04 (2.66) and 9.65 (4.57), respectively. The combination group had pain scores of 8.66 (4.66), 6.96 (4.38), and 7.62 (4.37), for 1-, 2-, and 3-month follow-up, respectively. The monotherapy group had pain scores of 8.17 (4.46), 7.82 (5.04), and 7.73 (4.25) for 1-, 2-, and 3-month follow-up, respectively. There was no significant difference between groups ( P = 0.65). Sant et al. 25 evaluated the efficacy of the combination of oral pentosan polysulfate and oral hydroxyzine compared to either agent alone, or placebo in patients with IC/BPS. A total of 121 patients were randomized to either receive 100 mg of pentosan polysulfate 3 times daily and hydroxyzine 50 mg nightly, 100 mg 3 times daily of pentosan polysufate alone, 50 mg nightly of hydroxyzine alone or placebo, for 24 weeks. Pain was measured using a scale (0–9) at baseline and at the 24-week follow-up. Baseline pain scores (SD) for combination group were 5.8 (1.1), PPS 6.3 (1.4), hydroxyzine 6.0 (1.0), and placebo 6.0 (1.3). The mean change (SD) in pain scores for the groups were −1.2 (1.9), −0.7 (1.8), −1.1 (1.9), and −0.9 (1.8), respectively. There were no significant difference between any of the groups. Due to the heterogeneity in studies, no quantitative analysis of secondary outcomes could be performed. Instead, a descriptive summary of findings is presented. Functional outcomes were measured in 2 of the included studies using the following scales: the Medical Short Form Survey (MSFS) and the Interstitial Cystitis Symptom Index (ICSI) (Table 4 ). Alexander et al. 1 assessed functional outcomes of the combination of ciprofloxacin and tamsulosin using the MSFS. They found no significant difference in functional outcomes when comparing the combination group to either of the monotherapy groups or placebo. Ozkidik 23 assessed functional outcomes of the combination of hyaluronic acid and chondroitin sulphate using the ICSI. There was no significant difference between groups when comparing combination group to monotherapy groups. Functional outcomes data from included studies. Quality of life was reported in 4 of the included studies using the following scales: NIH-CPSI, Health-Related Quality of Life (HRQoL), and Short-Form 36 (SF-36) (Appendix 3, http://links.lww.com/PR9/A319 ). Alexander et al. 1 used the NIH-CPSI QOL scale and found no difference between the combination group of ciprofloxacin and tamsulosin, compared to the monotherapy groups or placebo. Ziaee et al. 31 also used the NIH-CPSI QOL scale and found no difference between combination therapy of ofloxacin and allopurinol when compared to allopurinol for improving quality of life scores. Ozkidik 23 used the HRQoL scale and found a significant improvement in functional outcomes in the combination group of hyaluronic acid and chondroitin sulphate when compared to both monotherapy groups. Davis et al. 10 used the SF-36 scale and found that by the end of treatment, the combination group of intravesical and oral PPS showed significant improvement in all health-related qualify of life domains compared to baseline, whereas the monotherapy group only showed improvement in 3 domains (role/physical, bodily pain, vitality) compared to baseline. Although Labat et al. 16 reported that there was no difference in quality of life, pain-related restrictions, or sexual function, no numerical data were provided. Five studies reported on global impression of change, using the NIH-CPSI score, Patient Perception of Bladder Control (PPBC), and a global assessment questionnaire (Appendix 4, http://links.lww.com/PR9/A319 ). Alexander et al. 1 used the NIH-CPSI and found no difference between the combination of ciprofloxacin and tamsulosin, compared to either monotherapy group or placebo. Ziaee et al. 31 also used the NIH-CPSI and found no differences between the combination of ofloxacin and allopurinol compared to allopurinol alone. Ozkidik 23 used the PPBC and found no difference in scores between the combination group of hyaluronic acid and chondroitin sulphate compared to either monotherapy group. Davis et al. 10 used a global assessment questionnaire and found no difference between the combination group of intravesical and oral PPS when compared to oral PPS alone. Sant et al. 25 used the Wisconsin IC score and found no differences between the combination of PPS and hydroxyzine and either monotherapy agent or placebo. Symptom improvement was measured in 5 studies, using the NIH-CPSI urinary score, Pain Urgency Frequency Questionnaire (PUF), and direct questioning around symptoms (Appendix 5, http://links.lww.com/PR9/A319 ). Alexander et al. 1 used the NIH-CPSI urinary score and found no differences between the combination group of ciprofloxacin and tamsulosin compared to either monotherapy or placebo groups. Ziaee et al. 31 also used the NIH-CPSI urinary score and found no differences between ofloxacin and allopurinol group compared to allopurinol alone. Ozkidik 23 used the PUF scale and found a significant difference in the combination of hyaluronic acid and chondroitin sulphate compared to monotherapy groups. Davis et al. 10 asked patients about improvement in urgency and frequency and found significant improvements in the combination group of intravesical and oral PPS compared to oral PPS alone for these symptoms. Sant et al. 25 used the ICSI and found no differences between the combination group of PPS and hydroxyzine to either monotherapy agent or placebo. They did, however, find a significantly reduced voiding frequency in the combination group compared to the other groups ( P = 0.0037). Safety of interventions was inconsistently reported across studies. Only 5 studies reported the nature of adverse effects (AEs) encountered by patients. 1 , 10 , 16 , 23 Four out of 8 studies reported on the method of AE assessment, which included asking about symptoms directly 1 , 31 and via questionnaires. 25 , 28 There was no significant difference in the incidence of AEs or serious AEs when comparing intervention to placebo across all studies. There were no significant differences in the rate of withdrawals between combination groups and monotherapy groups across studies.

This systematic review evaluated the efficacy and safety of combination pharmacological therapy in treating conditions associated with chronic pelvic pain. These included chronic pelvic pain in women, CP/CPPS in men, and IC/BPS affecting women and men. Although 9 studies were included in this review, we found insufficient evidence to make definitive conclusions regarding the superiority of any 1 combination pharmacological therapy compared to monotherapy in managing chronic pelvic pain. None of the included studies reported a significant difference in reducing pain intensity for patients who received combination therapy as opposed to the monotherapy agent. There were no significant differences in most studies on secondary outcomes such as quality of life, functional outcomes, global impression of change, and symptom improvement. Due to significant heterogeneity in the pharmacological agents and chronic pain conditions being studies, quantitative meta-analyses could not be performed. The safety of combination therapy appears to be similar to that of monotherapy, as there were no significant differences in the rate of serious adverse events, adverse events, or withdrawals between groups across studies. Our review included studies from a variety of chronic pelvic pain conditions, including CP/CPPS, IC/BPS, endometriosis, hemorrhoids, and chronic pudendal neuralgia. The consistent finding across all studies in these conditions was that the combination of pharmacological therapy was not superior to monotherapy agents in reducing pain intensity. The proposed mechanism of combination therapy in reducing pain intensity is that agents from different drug classes, targeting different receptors may improve efficacy. There may be several reasons why these studies did not find a difference in combination therapy. First, there were only 1 to 2 studies investigating each pain condition we assessed. The inclusion of more studies, encompassing a larger cohort of patients, may have elucidated differences that were not found in the current review. Second, a few studies in our review utilized drugs from the same or similar drug class. Although this could theoretically provide a greater effect, it is more likely that using agents from different drug classes, which bind to different receptors thought to be associated with certain conditions, would produce a greater clinical effect. These combinations may also reveal a benefit in drug tolerability, an outcome that was not found in the present review. Finally, the studies in the present review only looked at a small fraction of the possible combination of pharmacological agents used in treating chronic pelvic pain. It may be that a different combinations of pharmacological agents could provide greater clinical efficacy in reducing pain than the monotherapy agents; however, further studies are needed to support this. In clinical practice, the most common approach of managing CPP involves a combination pharmacologic therapy. Patients are carefully selected, and the approach is most successfully employed by tailoring each patient's multimodal treatment regime to the patient's individual clinical phenotype and/or suspected mechanism of disease. This differs for each patient, and thus the specific combination used will also vary. As clinical trials utilize 1 combination for all patients, regardless of differences in phenotype or mechanisms, the true benefit may be masked by nonresponders who would benefit from a different combination of agents. There are several strengths of this review that are important to highlight. To our knowledge, this is the first systematic review evaluating combination pharmacological therapy for chronic pelvic pain. This review was performed according to a pre-registered protocol and in keeping with best practice for systematic reviews. The risk of bias in the included studies was also generally low, providing a reasonable degree of validity when interpreting results. The studies generally had an adequate treatment duration, which lends itself to extrapolation to clinical settings of chronic pain management. Our review included studies contributing to the largest burden in chronic pelvic pain, including chronic pelvic pain in women, CP/CPPS in men, and IC/BPS. Finally, this review provides a framework that can inform the development of future studies, highlighting key areas such as thorough pain score assessment and reporting, harms assessment and reporting, and robust study designs with larger sample sizes. Future RCTs should focus on selecting for subgroups of patients with similar clinical phenotypes or suspected mechanism of disease and tailor a combination approach specific to the patient. Alternatively, an a priori stratification of patient phenotypes could be used, so that 1 combination is not applied to all patients, as this would more closely reflect what is done in actual clinical practice. Other unique trial designs such as adaptive design RCTs, “n of one” studies, and prospective “real world” clinical practice studies may be the most optimal manner to evaluate combination pharmacologic therapy. These trials should also evaluate more relevant patient-related outcomes along with pain, to further elucidate the benefits of combination therapy. Finally, and most relevant to the evaluation of combination therapy, future trials should be designed such that the combination of interest (eg, “drug A + drug B”) is compared to each and every monotherapy component (eg, “drug A” alone and “drug B” alone) to be able to demonstrate the superiority of the combination vs monotherapy. 3 , 12 , 13 Our review was not without its limitations, which are important to acknowledge when interpreting the results. Given that this is a relatively underinvestigated area, only a limited number of studies were included in the review. Although our search strategy was designed with the intention of synthesizing evidence of combination therapies for a wide variety of pelvic pain conditions, it is possible that studies of irritable bowel syndrome and perhaps others that were not specifically named in the search strategy were not included. The studies included in this review generally had small sample sizes and did not report secondary outcomes as reliably as pain outcomes. Given the limited number of studies in this review, it was difficult to make any meaningful comparisons in treatment efficacy between women and men or across pain conditions being treated. In our systematic review, there is insufficient evidence to stipulate the superiority of combination pharmacological therapy to monotherapy in efficacy and safety for chronic pelvic pain. Based on the data available in this review, it appears that combination therapy is not associated with significant differences in clinical outcomes compared to monotherapy. If future proof-of-concept studies demonstrate that a given combination is superior to all monotherapy components, subsequent large, double-blind RCTs of such combinations in selected subpopulations of chronic pelvic pain in women, CP/CPPS in men, and IC/BPS are required to better elucidate the role of combination therapy in clinical settings. Larger, double-blind RCTs evaluating the role of combination pharmacological therapy in selected subpopulations of chronic pelvic pain in women, CP/CPPS in men, and IC/BPS are required to better elucidate the role of combination therapy in clinical settings. These RCTs would add to the body of literature in this setting and allow more definitive conclusions to be drawn.

Chronic pelvic pain is a highly prevalent and complex condition. It remains a multifaceted challenge as a result of its poorly understood etiologies, broad definitions, and predominantly empirical nature of its treatments, often resulting in unsatisfactory patient outcomes. 7 Three frequently studied pelvic pain disorders in the literature are chronic pelvic pain (CPP) in women, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men, and interstitial cystitis/bladder pain syndrome (IC/BPS). 7 Estimates of the prevalence and incidence of CPP, CP/CPPS, and IC/BPS are probably underreported, due to stigma surrounding these pain syndromes of the pelvic and urogenital area, an area often considered taboo, and provider disbelief and pain dismissal. 5 Within the domain of women's health, CPP is the most common reason for referral to women's health specialists, constituting up to 20% of all outpatient appointments in secondary care. 17 Its incidence in primary care, affecting 38 per 1000 women, is similar to that of back pain (41 per 1000). Estimates of global prevalence vary from 2.1% to 24%, 17 with estimates as high as 14.7% and 25% in the United States and United Kingdom, respectively. 9 , 19 , 32 In men, CP/CPPS is the most common urological disorder for those under 50 and stands as the third most common diagnosis for those over 50. 26 With a global prevalence of approximately 7.1%, up to 10% of men may experience symptoms at some point in their lives. 8 Chronic prostatitis/chronic pelvic pain syndrome accounts for approximately 1% of primary care visits and 8% of urology consultations in the United States, 8 with men reporting pain in the perineum, penis, testicles, scrotum, or the suprapubic region. Similarly, IC/BPS affects both genders but predominantly afflicts women, with prevalence estimates ranging from 3% to 7% in women and 2%-4% in men, totaling over 10 million affected individuals in the United States. 4 , 29 Some estimates suggest that approximately 90% of patients are women, and 95% of patients have a median age of 40 years. 4 In men, 17% of those diagnosed with IC/BPS are also found to have CP/CPPS. Due to the numerous contributing factors to chronic pain in the pelvic region, numerous medical interventions have been proposed for its treatment. Some of these include α-blockers, 5-α-reductase inhibitors, quinolones/tetracyclines, phytotherapy, nonsteroidal anti-inflammatory drugs, neuromodulators, opioids, muscle relaxants, cannabinoids, and various intravesical medical interventions. 6 , 14 , 15 Despite the wide array of pharmacological interventions available, monotherapy has not been found to be universally successful in treating chronic pelvic pain, pointing to a multimodal treatment approach. 18 , 21 , 22 In clinical practice, analgesic treatments are generally first introduced as monotherapy with a subsequent assessment of tolerability and beneficial effects. When a treatment is reasonably well tolerated but provides only partial benefit, 1 strategy involves combination therapy whereby a second agent is introduced in an “add-on” fashion. 12 The proposed benefit of combination therapy is that the adverse events of each individual agent can be minimized, while the efficacy can be combined, leading to better patient compliance and safety. 13 Combination pharmacotherapy has been studied in other pain conditions including neuropathic pain, 3 fibromyalgia, 30 cancer pain, 27 and arthritis 24 with some evidence of added benefit compared to monotherapy. Combination pharmacologic therapy is currently widely used in clinical practice for treating CPP, despite the lack of systematic reviews in the literature comparing combination therapy to monotherapy. Our systematic review sought to evaluate the efficacy and safety of combination pharmacological therapy for treatment of chronic pelvic pain, with the goal of assisting clinicians in the decision-making process when treating their patients.

Supplemental digital content associated with this article can be found online at http://links.lww.com/PR9/A319 .

M.M. has no conflicts to disclose. R.P. has no conflicts to disclose. U.W. serves on the External Consultant Board for the “NIH Preclinical Screening Platform for Pain” at the National Institutes of Health (NIH/NINDS). In her capacity as a special government employee of the US Food and Drug Administration (FDA), she has served as a voting member of the FDA Anesthetic and Analgesic Drug Products Advisory Committee. She serves as an elected member on the Council of International Association for the Study of Pain. In the past 3 years, she has received compensation for serving on advisory boards or for consulting activities for Aphrodite Health Inc., Wilmington, DE; Avenue Therapeutics Inc., New York, NY; Bayer Aktiengesellschaft, Leverkusen, Germany; Biohaven Pharmaceuticals, New Haven, CT; Hillhurst Biopharmaceuticals, Montrose, CA; Seikagaku Corporation, Tokyo, Japan and Syneos Health, Morrisville, NC, all unrelated to the submitted work. C.P. is a Research Consultant for Initiator Pharma and a Clinical and Research Consultant for Pelva Health. K.J. has no conflicts to disclose. J.C.N. has no conflict of interest in any of the subjects or interventions described in this review. R.C.D. has no conflicts to disclose. I.G. has received support from Vertex and Combigene and has received grants from the Canadian Institutes of Health Research, Physicians' Services Incorporated Foundation, and Queen's University. S.H. has no conflicts to disclose.