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Oral IC/BPS Agents

Category: Pharmacology, Bladder Pain & IC/BPS

Overview​

The 2022 AUA guideline (Statement 14) lists amitriptyline, cimetidine, hydroxyzine and pentosan polysulfate (PPS) as oral options, in alphabetical order with no hierarchy.[1] Evidence strength is Grade B for amitriptyline, cimetidine and PPS, and Grade C for hydroxyzine.[1] The previous numbered treatment tiers were removed; selection and combinations depend on symptoms, comorbidities and patient preferences.[1][2] EAU 2026 differs in emphasis: it strongly recommends amitriptyline (level 1b) and oral pentosan polysulfate (level 1a), weakly recommends adding subcutaneous heparin in low responders to pentosan (1b), rates cimetidine evidence as limited (2b), cites a placebo-controlled trial in which hydroxyzine did not show a significant effect, and strongly recommends against long-term oral corticosteroids. EAU notes that amitriptyline is limited by drowsiness and that nortriptyline is sometimes used instead.[20]

PPS requires particular reconsideration: the 2025 CUA guideline conditionally recommends against oral PPS, judging its small benefit unfavorable against potentially serious visual harm and cost. This differs from its retained option status in AUA 2022. AUA Statement 15 directs clinicians to counsel patients considering PPS about macular damage and vision-related injury.[1] For Hunner-lesion IC/BPS, CUA made no recommendation for or against cyclosporine because of insufficient evidence.[12]

For the broader condition (diagnosis, phenotyping, and the full multimodal algorithm), see IC/BPS.

Mechanism of Action​

Five distinct mechanistic classes target different points in the IC/BPS cascade:

AgentClassPrincipal mechanism
AmitriptylineTricyclic antidepressantCentral analgesia (NE/5-HT reuptake inhibition), antihistamine (H1), anticholinergic (M1), sodium-channel modulation
Pentosan polysulfate (PPS)Semisynthetic GAG analogProposed urothelial barrier protection; the clinical mechanism is not established
HydroxyzineH1 antihistamineMast-cell stabilization; histamine-H1 receptor blockade
CimetidineH2 antagonistMast-cell / H2 receptor effects; immune modulation (less well characterized)
Cyclosporine ACalcineurin inhibitorCalcineurin inhibition reduces T-cell activation; not a selective B-cell treatment

Agents in This Class​

Generic NameBrand / Key NamesRouteStatusNotes
AmitriptylineElavil (historical)POOff-labelOption when pain and sleep disturbance are treatment targets
Pentosan polysulfate sodiumElmironPOFDA-approved for relief of bladder pain or discomfort associated with IC (1996)[24]Only FDA-approved oral agent; maculopathy risk[1]
HydroxyzineAtarax, VistarilPOOff-labelSometimes selected for allergic/atopic symptoms; efficacy uncertain
CimetidineTagametPOOff-labelMany CYP450 drug interactions
Cyclosporine ANeoral, Sandimmune, GengrafPOOff-labelSelected refractory cases; nephrotoxicity and monitoring burden. Neoral and Sandimmune are not bioequivalent; switch only under prescriber supervision, with renal-function/BP monitoring and drug levels as indicated by the regimen.[19]

Indications in Reconstructive Urology​

Primary: symptom treatment for patients meeting IC/BPS criteria, alongside education, self-care and other appropriate therapies.[1]

Phenotype-directed use:

  • Hunner-lesion IC/BPS. AUA Statement 16 (Option, Grade C) allows oral cyclosporine A for patients with Hunner lesions that are refractory to fulguration and/or triamcinolone. In the guideline's evidence review, a retrospective three-center series (44 patients; mean follow-up 20.8 months) defined response as marked improvement on a seven-point global response assessment at two centers or at least a 50% ICSI decrease at one center.[23] Initial responses occurred in 29/34 (85%) patients with Hunner lesions and 3/10 (30%) without.[1] Six Hunner-lesion responders stopped cyclosporine because of adverse events, leaving 23/34 (68%) with treatment success; the phenotype comparison remains observational.[1] Its toxicity requires careful selection; comparative evidence for the Hunner phenotype is limited.[1][4][12]
  • Pain-dominant, sleep-disturbed, or comorbid neuropathic-pain presentations. Amitriptyline may be selected for its analgesic and sedating effects.[5]
  • Patients with systemic allergies. Hydroxyzine may be considered, but the placebo-controlled trial did not show a statistically significant benefit.[1][6]
  • Non-Hunner disease. Choose a time-limited trial according to symptoms and harms; no oral drug reliably predicts response. Discuss the updated PPS benefit–risk balance before prescribing.[1][12]

Dosing & Administration​

Doses listed are for reference only. Confirm with current guidelines and institutional protocols. TCA, antihistamine, and immunosuppressant dosing must be individualized to patient comorbidities, concomitant medications, and renal or hepatic function.

AgentStarting doseTitration targetDuration before judging efficacy
Amitriptyline10–25 mg PO qhsUp to 75–100 mg qhs as tolerated (the range the AUA guideline describes)[1]12 weeks (Foster trial primary assessment)[5]
Pentosan polysulfate100 mg PO TID with water, at least 1 hour before or 2 hours after mealsNo routine titrationReassess at 3 months; the label allows another 3 months if unimproved but tolerating. Benefit–risk beyond 6 months in nonresponders is unknown.[13]
Hydroxyzine10–25 mg PO qhsCommon IC/BPS regimens use up to 50 mg qhs; assess sedation, age and QT riskReassess response and tolerability within weeks.[15]
Cimetidine400 mg PO BID—Reassess at 3 months, the endpoint of the cited trial.[1][10]
Cyclosporine APublished IC/BPS regimens commonly use 2–3 mg/kg/day divided BIDSpecialist-adjusted dosing according to renal function, BP, interactions and protocol-specific drug levelsAssess benefit and toxicity regularly; not a routine empiric prescription.[4][15]

General principles:

  • Start low and titrate, particularly for TCA and hydroxyzine where sedation is dose-limiting
  • For PPS, the label recommends a pretreatment retinal examination for patients with pre-existing eye disease and suggests OCT and fundus autofluorescence within six months of starting for all patients, with periodic follow-up.[13]
  • For cyclosporine, check baseline and serial BP, renal function (Cr, eGFR), CBC, LFTs and electrolytes (Mg, K), with drug-level monitoring determined by the specialist regimen.[19]
  • Do not force amitriptyline escalation when anticholinergic effects or sedation outweigh benefit
  • Gabapentin (300–2100 mg/day in three divided doses) appeared in the 2016 CUA guideline as an option for IC/BPS with neuropathic pain refractory to conservative therapies; it is not among the AUA 2022 oral options listed above.[15]
  • Sequential or combination trials are reasonable[1][2]

Contraindications & Precautions​

Amitriptyline​

  • Label contraindications: prior hypersensitivity, concurrent MAOI use (allow at least 14 days after stopping an MAOI), and cisapride (QT prolongation and arrhythmia). The label does not recommend use during the acute recovery phase after myocardial infarction.[16]
  • Caution: narrow-angle glaucoma, BPH with retention risk, cardiac conduction disease and QT-prolonging co-medication, serotonergic polypharmacy (serotonin syndrome; SSRIs also inhibit CYP2D6 and raise tricyclic levels), elderly (anticholinergic burden, falls). The boxed warning calls for close monitoring for clinical worsening, suicidality or unusual behavior in patients of all ages, especially after initiation or dose changes; short-term trials in depression and other psychiatric disorders found increased suicidality in young adults.[16]
  • Typical side effects: dry mouth, constipation, sedation, weight gain, orthostasis, urinary retention (ironic in this population)

Pentosan polysulfate​

  • Label warning (not a boxed warning): potentially irreversible pigmentary maculopathy. Cumulative exposure is a risk factor, and retinal changes may progress after stopping treatment. The label notes that most reported cases followed three or more years of use, but cases have occurred after shorter use.[7][8][9][13]
  • US label screening: obtain a detailed ophthalmologic history (consider genetic testing if there is a family history of hereditary pattern dystrophy). With pre-existing ophthalmologic conditions, the label recommends a comprehensive baseline retinal examination, including color fundus photography, OCT and autofluorescence, before starting. For all patients, the label suggests baseline OCT and fundus autofluorescence within 6 months and periodic follow-up; it does not set a universal annual interval.[13] If retinal pigmentary changes develop, reevaluate PPS under the US label. The 2024 ASRS ReST Committee report advises immediate discontinuation if new macular changes are consistent with PPS maculopathy.[21] Continue retinal follow-up after cessation because changes may progress.[13]
  • Bleeding risk. PPS has weak anticoagulant activity; use caution with concurrent anticoagulants, NSAIDs, bleeding disorders or a history of heparin-induced thrombocytopenia.[13]
  • Hepatic dysfunction reported; consider liver disease and abnormal tests in the prescribing assessment.

A Korean claims-based cohort included 103,553 PPS users and 205,792 nonusers with cystitis. PPS exposure was associated with subsequent maculopathy (adjusted HR 1.34, 95% CI 1.31–1.38).[14]

Hydroxyzine​

  • Label contraindications. Early pregnancy, prolonged QT interval, and hypersensitivity to hydroxyzine, cetirizine or levocetirizine. The label also advises against use while breastfeeding.[17]
  • Caution: QT-prolonging co-medication or risk factors (congenital long QT, recent MI, bradyarrhythmia), elderly (start low; sedation, anticholinergic burden). The label warns that hydroxyzine potentiates CNS depressants, so reduce narcotic, non-narcotic analgesic and barbiturate doses accordingly. Stop hydroxyzine at the first rash, worsening of a pre-existing skin reaction or other hypersensitivity sign; do not resume if acute generalized exanthematous pustulosis is suspected.[17]

Cimetidine​

  • Contraindication: hypersensitivity only. Interactions: cimetidine inhibits hepatic microsomal (CYP450) drug metabolism. The label names warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline and metronidazole. Review the full medication list before prescribing.[18]
  • Caution: advancing age (50 years or older) or preexisting renal or liver disease (reversible confusion), severe renal impairment (label dose 300 mg every 12 hours)[18]

Cyclosporine A​

  • Contraindicated (Neoral label, rheumatoid arthritis and psoriasis indications; the closest label analogue for non-transplant use): abnormal renal function, uncontrolled hypertension, malignancy, and hypersensitivity. In psoriasis the label also excludes concomitant PUVA or UVB, methotrexate and other immunosuppressants. Infection is a precaution, not a listed contraindication.[19]
  • Monitoring-dependent: baseline and repeated BP, renal function, electrolytes and other laboratory assessment under the prescribing specialist. For IC/BPS, drug-level targets, including trough levels, and monitoring intervals depend on the regimen.[1][15]
  • Major drug interactions: cyclosporine is extensively metabolized by CYP3A4 and is a P-glycoprotein substrate, so inhibitors and inducers can change its exposure; macrolides, azoles and grapefruit can raise cyclosporine levels. Cyclosporine can increase exposure to several statins, with reported myopathy and rhabdomyolysis during coadministration.[19]
  • Long-term risks: nephrotoxicity, hypertension, gingival hyperplasia, hypertrichosis, increased infection and malignancy risk. Avoid live vaccines during treatment.[19]

Perioperative Considerations​

AgentPeriop actionRationale
AmitriptylineGenerally continue; document for anesthesiaAnticholinergic burden, QT, orthostasis — coordinate with anesthesia if prolonged operation or cardiac comorbidity
PPSAgree stop/restart timing with the procedural teamWeak anticoagulant activity; the label advises discussing surgery, with no stated 7-day hold.[13]
HydroxyzineGenerally continue; tell anesthesiaReview additive sedation with anesthetics and QT-prolonging antiemetics (e.g., ondansetron or droperidol), especially with other QT risk factors.[17]
CimetidineContinue; flag CYP450 interactions to pharmacyCan alter anesthetic drug levels
Cyclosporine ADiscuss with transplant/rheum prescribing colleaguePerioperative infection risk; wound healing; nephrotoxicity under hemodynamic stress — do not hold without discussion given flare risk

Evidence Summary​

AgentEvidenceKey reference
PPSFDA-approved, but RCT efficacy is inconsistent and retinal toxicity changes its benefit–risk balance. The AUA guideline reviewed seven randomized trials (more than 500 patients). PPS response ranged from 21% to 56% across those trials, but the 21% came from a PPS–cyclosporine comparison without a placebo arm; placebo response in placebo-controlled trials ranged from 13% to 49%. A pooled analysis of five trials with PPS and placebo arms gave a relative risk of 1.69 (95% CI 1.16–2.46). It notes some evidence of lower efficacy with Hunner lesions.[1] CUA 2025 conditionally recommends against use.[12]Sant 2003 ICCTG[6]; Hall 2025[7]
AmitriptylineThe AUA guideline cites one older randomized trial in which 63% of amitriptyline patients versus 4% of placebo patients were clinically significantly improved at 4 months; the trial’s primary endpoint was change in the O’Leary–Sant symptom/problem index. Anticholinergic adverse events occurred in 92% versus 21%, respectively; dry mouth occurred in 79% of amitriptyline patients.[1][22] In Foster 2010, 271 treatment-naïve participants in both arms received education and behavioral modification; at 12 weeks, intention-to-treat global response was 55% with amitriptyline versus 45% with placebo (p=0.12).[5] A subgroup reaching at least 50 mg showed 66% vs 47% response, but that subgroup comparison was not prespecified.Foster 2010[5]; Di 2021[3]
HydroxyzineSant 2003 ICCTG RCT — hydroxyzine alone or with PPS did not show significant benefit over placebo. Commonly used on expert-opinion basis.Sant 2003[6]
CimetidineSmall RCT (Thilagarajah 2001, 36 randomized, 34 completed, 3 months) — pain and symptom improvement vs placebo. Limited subsequent validation.Thilagarajah 2001[10]
Cyclosporine AA small open-label randomized comparison favored cyclosporine over PPS (adverse events were more frequent with cyclosporine, including hypertension and raised creatinine).[1] A 23-RCT network meta-analysis found lower ICSI and ICPI scores with cyclosporine than placebo.[3] Toxicity limits use.[12]Sairanen 2005[4]; Di 2021[3]
Cochrane network meta-analysis81 RCTs (4,674 participants), mostly small studies. Low or very low certainty for most treatment comparisons; benefit for PPS and several other treatments remains uncertain.Imamura 2020[11]

Practical Pearls​

  • Amitriptyline dosing. Start at 10 mg qhs and titrate gradually as tolerated; Foster 2010 titrated toward a maximum of 75 mg over six weeks and assessed response at 12 weeks.[5] Titrate toward 75–100 mg only if tolerating, as described by the AUA guideline.[1]
  • PPS counseling is non-negotiable. The maculopathy conversation (and documentation of it) must happen before the first prescription. Arrange retinal assessment according to the label and the patient's ocular history. Some patients will decline PPS on this basis, which is a reasonable choice.[7][8]
  • Cimetidine evidence. A 36-patient placebo-controlled trial assessed cimetidine 400 mg twice daily for 3 months.[10] Select among H2 blockers with attention to cimetidine's drug interactions and limited comparative evidence.[1][10][18]
  • Cyclosporine monitoring. Use oral cyclosporine in a setting able to adjust dosing and closely monitor blood pressure, renal function, adverse effects and drug levels as the regimen requires.[4][12][23]
  • Reassess benefit and harms. Agree an agent-specific review point and stop ineffective treatment. If PPS is chosen after counseling, follow its 3- and 6-month reassessment instructions rather than continuing an ineffective course indefinitely.[1][13]
  • Sequential trials are normal. Patients may cycle through 2–3 agents before finding one that helps. Document why each was chosen and why each was discontinued.
  • Combination therapy is common in practice even without strong trial support, for example amitriptyline plus PPS, or amitriptyline plus hydroxyzine for overlapping sleep or allergy symptoms.[1][2] With amitriptyline plus hydroxyzine, assess additive sedation, anticholinergic effects and QT risk.[16][17]

See Also​

References​

1. Clemens JQ, Erickson DR, Varela NP, Lai HH. "Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome." J Urol. 2022;208(1):34-42. doi:10.1097/JU.0000000000002756

2. Chermansky CJ, Guirguis MO. "Pharmacologic Management of Interstitial Cystitis/Bladder Pain Syndrome." Urol Clin North Am. 2022;49(2):273-282. doi:10.1016/j.ucl.2022.01.003

3. Di XP, Luo DY, Jin X, et al. "Efficacy and Safety Comparison of Pharmacotherapies for Interstitial Cystitis and Bladder Pain Syndrome: A Systematic Review and Bayesian Network Meta-Analysis." Int Urogynecol J. 2021;32(5):1129-1141. doi:10.1007/s00192-020-04659-w

4. Sairanen J, Tammela TL, Leppilahti M, et al. "Cyclosporine A and Pentosan Polysulfate Sodium for the Treatment of Interstitial Cystitis: A Randomized Comparative Study." J Urol. 2005;174(6):2235-8. doi:10.1097/01.ju.0000181808.45786.84

5. Foster HE Jr, Hanno PM, Nickel JC, et al. "Effect of Amitriptyline on Symptoms in Treatment Naïve Patients With Interstitial Cystitis/Painful Bladder Syndrome." J Urol. 2010;183(5):1853-8. doi:10.1016/j.juro.2009.12.106

6. Sant GR, Propert KJ, Hanno PM, et al. "A Pilot Clinical Trial of Oral Pentosan Polysulfate and Oral Hydroxyzine in Patients With Interstitial Cystitis." J Urol. 2003;170(3):810-815. doi:10.1097/01.ju.0000083020.06212.3d

7. Hall BP, Shiromani S, Vanderbeek BL, et al. "Pentosan Polysulfate Maculopathy: Clinical Considerations, Pathobiology, and Causality." Prog Retin Eye Res. 2025;109:101400. doi:10.1016/j.preteyeres.2025.101400

8. McGwin G, MacLennan P, Owsley C. "Association Between Pentosan Polysulfate Sodium and Retinal Disorders." JAMA Ophthalmol. 2022;140(1):37-42. doi:10.1001/jamaophthalmol.2021.4778

9. Lindeke-Myers A, Hanif AM, Jain N. "Pentosan Polysulfate Maculopathy." Surv Ophthalmol. 2022;67(1):83-96. doi:10.1016/j.survophthal.2021.05.005

10. Thilagarajah R, Witherow RO, Walker MM. "Oral Cimetidine Gives Effective Symptom Relief in Painful Bladder Disease: A Prospective, Randomized, Double-Blind Placebo-Controlled Trial." BJU Int. 2001;87(3):207-12. doi:10.1046/j.1464-410x.2001.02031.x

11. Imamura M, Scott NW, Wallace SA, et al. "Interventions for Treating People With Symptoms of Bladder Pain Syndrome: A Network Meta-Analysis." Cochrane Database Syst Rev. 2020;7:CD013325. doi:10.1002/14651858.CD013325.pub2

12. Doiron RC, Tadayon B, Violette PD, et al. "2025 Canadian Urological Association Guideline: Selected treatment recommendations for interstitial cystitis/bladder pain syndrome." Can Urol Assoc J. 2025;19(4):90–103. doi:10.5489/cuaj.9182

13. Janssen Pharmaceuticals. ELMIRON (pentosan polysulfate sodium) US prescribing information. Label effective September 2024.

14. Kim MS, Choi YJ, Ji E, et al. "Association between Pentosan Polysulfate and Subsequent Maculopathy: Insights from a Nationwide Population-Based Study in Korea." Ophthalmology. 2025;132(1):108–114. doi:10.1016/j.ophtha.2024.07.027

15. Cox A, Golda N, Nadeau G, et al. "CUA guideline: Diagnosis and treatment of interstitial cystitis/bladder pain syndrome." Can Urol Assoc J. 2016;10(5–6):E136–E155. Full text. Historical dose examples; updated treatment positioning is in the 2025 guideline above. doi:10.5489/cuaj.3786

16. Sun Pharmaceutical Industries. Amitriptyline hydrochloride tablets US prescribing information. DailyMed. Accessed September 24, 2026.

17. Hydroxyzine hydrochloride tablets US prescribing information. DailyMed. Accessed September 24, 2026.

18. Mylan Pharmaceuticals. Cimetidine tablets US prescribing information. DailyMed. Accessed September 24, 2026.

19. Novartis. NEORAL (cyclosporine) US prescribing information. DailyMed. Accessed September 24, 2026.

20. Engeler D, Baranowski AP, Berghmans B, et al. EAU Guidelines on Chronic Pelvic Pain. European Association of Urology; limited update March 2026. Guideline

21. Girgis JM, Baumal CR, Witkin AJ, et al. "Update on Retinal Drug Safety: Proceedings of the ASRS ReST Committee Webinar Part 1." J Vitreoretin Dis. 2024;8(5):500–507. doi:10.1177/24741264241261441

22. van Ophoven A, et al. "A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis." J Urol. 2004;172(2):533-536. doi:10.1097/01.ju.0000132388.54703.4d

23. Forrest JB, Payne CK, Erickson DR. "Cyclosporine A for refractory interstitial cystitis/bladder pain syndrome: experience of 3 tertiary centers." J Urol. 2012;188(4):1186–1191. doi:10.1016/j.juro.2012.06.023

24. US Food and Drug Administration. Elmiron (pentosan polysulfate sodium): orphan drug approval record. Marketing approval September 26, 1996. FDA record.