Table 2.

Prospective Studies of Pharmacological Interventions for AIMSS

Author [Ref.]	Study Location	Study Design	Intervention, Na	Control(s), Na	Co-Interventions	Duration	Main Outcome Measure(s)	Tolerability/ Safety	Main Findings
Endocrine or Hormonal Interventions
Birrell & Tilley, 2009b	Australia	RCT/PG	Testosterone 80 mg (n = 30) Testosterone 40 mg (n = 30)	Placebo (PBO) (n = 30)	Unspecified	12 weeks	VAS	- No significant androgenic side-effects	- VAS scores reduced (improved) for all groups – 70% for 80 mg testosterone group (p=0.04 vs PBO), 43% for 40 mg testosterone group (p=0.06 vs PBO), and 35% for PBO.
Cathcart-Rake et al, 2021	USA	RCT/PG	Testosterone pellets or Testosterone gelc (n = 80)	Placebo pellets or gelc (n = 77)	Unspecified	6 months	Average pain rating (0–10-point scale) using the modified BPI-AIA item #3	- No significant differences between groups in hot flash scores or frequencies.	- No significant between-group differences in average joint pain at 3- and 6 months. - No significant differences in proportion of subject reporting a > 1-point improvement in BPI-AIA average pain score at 3 months.
Liu et al, 2014	China	RCT/PG	Calcitonin 200 IU + vitamin D 600 mg (n = 42)	Vitamin D 600 mg (n = 40)	Unspecified	3 months	VAS	- Unspecified.	- Significantly greater improvement in VAS scores with calcitonin + vitamin D relative to vitamin D only.
Analgesic or Anti-Inflammatory Medications
Kubo et al, 2012	Japan	Pre/post	Prednisolone 5 mg (n = 27)	None	Unspecified	2 months	VAS, investigator-developed questionnaired	- Unspecified	− 67% of patients reported improved pain using VAS at 1 week, 63% at 1 month, 52% at 2 months. Differences from baseline were significant at 1 week and 1 month, but not at 2 months. - 41% and 33% of subjects reported amelioration of symptoms at 1- and 2 months, respectively.
Martinez et al, 2022	USA	NRT/PG	Sulindac 150 mg (twice daily) (n = 43)	Observation only (n = 40)	Low-dose aspirin was permitted (< 81 mg/day)	12 months	BPI, WOMAC, FACT-G	- Most common adverse effects were grade 1 and 2 nausea, abdominal pain, or reflux; one case each of transient pancreatitis and cerebral hemorrhage (in patient with amyloid angiopathy) occurred as SAE’s.	- Significant improvement from baseline with sulindac in WOMAC pain, stiffness, and physical function subscales, but not BPI-SF worst pain scores. - 35% of participants assigned to sulindac with above-median baseline WOMAC total scores experienced > 50% improvement in WOMAC and FACT-G total scores. - No significant improvement from baseline in musculoskeletal symptoms or quality of life measures over 12 months in the observation group.
Neuromodulatory Medications
Henry et al, 2011	USA	Pre/post	Duloxetine 60–120 mg following titrationd (n = 35 enrolled)	None	Participants taking stable doses of medication for paine at enrollment were allowed to continue them.	8 weeks	BPI, VAS, HAQ, CES-D (depression), Menopause-Specific Quality of Life questionnaire, Hot Flash Related Daily Interference Scale, PSQI	- The most common adverse effects were fatigue, drowsiness, nausea, dry mouth, constipation, and headache.	− 72.4% achieved >30% decrease in average pain score at 8 weeks. - Of the 23 completers, 21 (91.3%) experienced at least a 2-point absolute decrease in average pain and a mean percent reduction in average pain of 60.9%. - Significant improvement in HAQ, hot flash interference, depression, and sleep scores.
Henry et al, 2018 and Schnell et al, 2021	USA	RCT/PG	Duloxetine 60 mg following titration (n = 127)	Placebo (n = 129)	Unspecified	12 weeks	BPI, WOMAC, M-SACRAH, Global Rating of Change Scale (pain), FACT-ES Trial Outcome Index, PHQ-9 (depression)	− 23.4% of duloxetine-treated subjects reported an adverse event. The most common included fatigue, nausea, headache, dry mouth, muscle aches, hot flashes, insomnia, diarrhea, dizziness, and constipation.	- Significantly greater improvement in average pain score with duloxetine than placebo at each time point (weeks 2–12). - Significantly higher rates of clinically meaningful improvement (>2 point reduction) in pain with duloxetine than placebo at week 6 (68% vs 49%), but not at weeks 2 (52% vs 40%) or 12 (68% vs 59%). - Significant advantages with duloxetine over placebo were documented for BPI worst pain and pain interference scores using the BPI; WOMAC functioning, pain, and stiffness scores; and M-SACRAH scores; functional quality of life and global rating of change scores. - No significant between-group differences in PHQ-9 (depression) scores. - A higher proportion of subjects reported perception of treatment as beneficial with duloxetine than placebo (73.3% vs 41.8%) despite no statistically significant between-group difference FACT-ES scores.
Therapeutic Switching to an Alternative Aromatase Inhibitor
Briot et al, 2010	France	Pre/post	Switch to letrozole 2.5 mg/day after 1 month washout (n = 179)	None	Patients could continue “minor” analgesics and “moderate” opioids	6 months	Discontinuation of letrozole due to severe musculoskeletal symptoms	- Not reported.	− 72.5% of enrollees were still taking letrozole after 6 months. - 28.5% discontinued letrozole due to musculoskeletal symptoms. - 15.3% reported having no joint pain.
Kadakia et al, 2017	USA	Otherf	Switch from letrozole to exemestane (n = 34) or from exemestane to letrozole (n = 49)	None	Unspecified	3 months following initiation of second AI	VAS, HAQ, EuroQOL (quality of life), CES-D (depression), HADS-A (anxiety)	- Not reported.	- VAS mean change in pain ratings with first AI and second AI were similar (0.8 vs −0.2), but differences were not significant. - Patients who discontinued their first AI medication reported less negative impacts on functional status, depression, and vasomotor symptoms during treatment with the second AI.
Other Pharmacological Interventions
Alhanafy et al, 2018	Egypt	Pre/post	Furosemide 20 mg + spironolactone 50 mg (n = 50)	None	Patients could continue NSAIDs, COX-2 inhibitors, and/or bisphosphates	4 weeks	WOMAC (lower extremity pain) and DASH (upper extremity pain)	- Four subjects with morning diuresis that interfered with work, 3 with grade 1 fatigue, 5 with grade 1 nausea.	- Significantly improved WOMAC total, pain, functioning, and stiffness scores. - Significantly improved DASH total, functional, and activity scores but no significant improvement in DASH pain score.
Fleege et al, 2024	USA	Pre/post	CBD oral solutiong, maximum tolerated dose (n = 39)	None	Unspecified	15 weeks	BPI, PROMIS physical function and social roles and activities scales	- Five discontinued due to adverse events; no grade 3–4 toxicities.	- Significantly improved BPI worst pain scores from baseline for all 39 participants. - 60.7% of completers reported improvement in BPI worse pain scores by > 2 points from baseline. - Significant improvements from baseline in PROMIS physical function and participation in social roles and activities scores.
Zhang et al, 2010	China	Pre/post	Thymosin alpha-1 SQ, 1.6 mg	None	Unspecified	4 weeks	BPI, WOMAC, FACT-G, 11-point Likert scale rating subjective pain intensity	- Not reported.	- Significantly improved BPI-SF worst pain, pain severity, and pain-related functional interference scores. - Significantly improved COMAC functional subscale and FACT-G physical well-being scores.
Zylla et al, 2024h	USA	RCT/PG	CBD topical balm, 2210 mg CBD:< 0.3% THC (n = 10)	Delta-9-THC predominant balm, 375 mg THC:< 20 mg CBD (n = 10)	Unspecified	2 weeks	BPI, M-SACRAH, PRO-CTCAE measures	- One subject discontinued due to greasy texture of the balm.	- Improvements in BPI average pain and pain interference scores and M-SACRAH scores were observed in both treatment arms, but statistical comparisons (within and between subjects) were not reported.

Notes: ^a Refers to subjects whose data were analyzed unless otherwise specified; ^b Results were published only in abstract form. ^c Study protocol was amended to allow for the substitution of testosterone topical gel or gel placebo, each applied daily for 6 months. ^d Investigator-developed questionnaire consisted of 6 items assessing to what degree “stiffened joint pain” weighed on the respondent’s mind, which joints were affected, the degree their pain intensity when using the VAS, how much joint pain affected the respondent’s quality of life, when anastrozole or letrozole treatment was initiated, and when symptoms of arthralgia appeared. ^d Duloxetine was initiated at a dose of 30 mg/day for 7 days, followed by titration to an initial target dose of 60 mg daily for 21 days. Subjects then had the option of continuing the 60 mg/day dose or increasing the dose to 60 mg twice daily. Those who could not tolerate duloxetine 60 mg/day were discontinued from the study. ^e Includes NSAIDs, COX-2 inhibitors, opioids, gabapentin, pregabalin, cyclobenzaprine, or glucosamine chondroitin, if they were being taken at the time of enrollment. Otherwise, subjects could take up to 2 g of acetaminophen daily for pain and up to 325 mg of aspirin daily for cardiac prophylaxis. ^f In original trial, patients were randomized to letrozole or exemestane. An amendment to the protocol allowed patients who could not tolerate their assigned AI to switch to the other study-provided AI. Such patients discontinued the first AI and remained off any AI therapy during a washout period lasting 2–8 weeks. Following washout, patients started treatment with the second AI until discontinuation for any reason during follow-up. ^g The cannabidiol (CBD) oral solution formulation used in this study is approved in the US for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. ^h This trial was listed as active/not recruiting on ClinicalTrials.gov on the literature search date. The information presented in this table was available from a conference abstract (see reference list).

Abbreviations: BPI-AIA, Brief Pain Inventory for Aromatase Inhibitor Arthralgia; CBD, cannabidiol; COX-2, cyclo-oxygenase-2; DASH, Quick Disabilities of the Arm, Shoulder, and Hand scale; FACT-ES, Functional Assessment of Cancer Therapy-Endocrine Scale; FACT-G, Functional Assessment of Cancer Therapy-General Scale; HAQ, Health Assessment Questionnaire; NRT/PG, non-randomized clinical trial (parallel-group design); NSAIDs, non-steroidal anti-inflammatory drugs; PSQI, Pittsburgh Sleep Quality Index; PRO-CTCAE, National Cancer Institute Patient Reported Outcomes Common Terminology Criteria for Adverse Events measures; PROMIS, Patient-Reported Outcomes Measurement Information System measures; RCT/PG, randomized controlled trial (parallel-group design); SAE, serious adverse event; SQ, subcutaneous delivery; THC, tetrahydrocannabinol; VAS, pain visual analog scale; WOMAC, Western Ontario and McMaster Universities index.