{"paper_id":"c2bc265f-ade5-4570-8edf-7b61253bb19c","body_text":"1 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nKey points\n• Chronic pelvic pain is a common and complex condition that significantly affects women’s quality of life.\n• Neuropathic pain and nociplastic pain are important components in the pain picture of these patients and \nshould be considered in clinical treatment.\n• Oral neuromodulators, antidepressants and anticonvulsants for the control of neuropathic and nociplas-\ntic pain should be present in the therapeutic arsenal of the gynecologist who treats patients with chronic \npelvic pain.\n• Pregabalin is the medication with the best pharmacokinetic profile; nortriptyline has the best adverse ef -\nfects profile; duloxetine is the most widely used and has the lowest risks; and venlafaxine should be used \nas a second-line inhibitor.\n• Although the drug classes can be combined to reduce the total doses and minimize side effects, maximiz-\ning the analgesic effect, monotherapies are recommended as the first line to avoid polypharmacy.\nRecommendations\n• We recommend the following order of priority as first-line treatment for neuropathic pain: 1) gabapentinoids; \n2) tricyclic antidepressants; 3) serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants.\n• We recommend the following order of priority as first-line treatment for nociplastic pain: 1) SNRI antide-\npressants; 2) gabapentinoids; 3) tricyclic antidepressants.\n• The use of cannabinoids should be restricted to academic research settings adhering to rigorous scientific \nprotocols until robust scientific evidence is published.\n• There is no time limit for maintaining treatment. As a rule, we recommend a period of at least six months \nand a maximum of 12 months. After that, and in accordance with the patient and other coping strategies, \ngradual discontinuation should be discussed;\n• The following should always be kept in mind: 1) achieving the lowest possible pain scores; 2) using the \nsmallest possible amount of medication; 3) using the lowest possible dose of each medication; 4) min-\nimizing side effects; 5) maximizing patient adherence; 6) reinforcing coping mechanisms and positive \nthinking.\nFEBRASGO POSITION STATEMENT\nUse of oral neuromodulators in chronic pelvic \npain\nNumber 8 – 2025\nDOI: http://dx.doi.org/10.61622/rbgo/2025FPS8\nThe National Specialized Commission on Endometriosis of the Brazilian Federation of Gynecology \nand Obstetrics Associations (Febrasgo) endorses this document. Content production is based on \nscientific evidence on the proposed theme, and the results presented contribute to clinical practice.\nBackground\nChronic pelvic pain is a common and complex condi-\ntion that can negatively affect people’s quality of life. \nVarious associated diseases can lead to symptoms \nthrough diverse mechanisms. In clinical practice, in ad-\ndition to seeking a specific diagnosis, it is essential to \ntypify the pain perceived by the patient. This is crucial \nin planning the therapeutic approach and consequent-\nly, achieving better medium and long-term outcomes.(1)\nPain can be simplified and classified as noci -\nceptive (also known as inflammatory), neuropath-\nic and nociplastic. Other categories can be listed, \nbut are beyond the scope of this statement. In the \nfirst case, it is triggered predominantly by peripher -\nal mechanisms directly induced by the underlying \ndisease(s). Thus, treating the underlying disease \nand using adjuvant analgesics from the non-steroi -\ndal anti-inflammatory drug (NSAID) class is gener -\n\n2  FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nUse of oral neuromodulators in chronic pelvic pain\nally effective for curing and/or controlling pain for \na relatively long period. (2) In the case of neuropath-\nic pain, the primary condition may also be directly \nresponsible for the neurological impairment. Thus, \nits treatment often results in substantial improve-\nment in pain, but neurological damage often per -\nsists and personalized adjuvant treatment must \nbe instituted. In this case, NSAIDs are not effective \nand may even lead to an increase in the perception \nof pain. Gabapentinoids have proven to be the most \neffective drugs in relieving this symptom, but anti -\ndepressants have excellent results that have been \nknown for a long time.\nAs should be evident from everyone’s clinical \nexperience, specific treatment of these “prima -\nry” diseases does not always result in the cure or \nprolonged control of painful symptoms. This is \ndue, at least in part, to the involvement of the cen-\ntral nervous system (CNS) in the pathophysiology of \nchronic pain.(3) The pain resulting from this condition \nis called nociplastic and is triggered by changes in \nthe CNS, the main one being central sensitization \n(CS). Briefly, CS is a process in which the individual \nbecomes more sensitive to pain due to the reduction \nor loss of effectiveness of the inhibitory modulation \nsystem. Perhaps the most curious and particular \nthing about this condition is that it is the primary \ncause of the perpetuation of chronic pain. In other \nwords, in this case, the painful symptom does not de-\npend on a possible primary triggering cause. Even if \nit is completely eliminated, the symptoms persist. (4) \nThe study of nociplastic pain has been the focus in \nthe investigation of processes that trigger and main-\ntain chronic pain. Clinically, it has been associated \nwith symptoms such as changes in mood, memory \nand sleep patterns, and fatigue.(5)\nThe medications we will discuss in this state-\nment are part of the arsenal we can use to provide \nsymptomatic relief to patients and have the greatest \nscientific basis in the current literature.\nBefore delving into a specific discussion on the \ntopic, it is important to emphasize the vast and rap-\nidly expanding field of pain pathophysiology. It is es-\nsential that we have the curiosity and responsibility \nto always keep ourselves updated. It is also important \nto emphasize two additional points. The first is that \nwe do not intend to exhaust the topic and/or pres-\nent all the possibilities of adjuvant treatments. We \nonly present considerations of the medications that \nhave proven to be the most effective in controlling \nchronic pelvic pain, whether as adjuvant or first-line \ntreatment, or that have had increasing media appeal. \nWe will focus on three classes: antidepressants, gab-\napentinoids and cannabinoids. The second point are \nthe several types of non-drug treatments included in \nthe therapeutic arsenal that play an important role \nin the lasting relief of symptoms. These modalities \nshould not be underestimated and be used as adju -\nvant measures whenever possible.\nAntidepressants. When and \nhow to use them?\nAntidepressants have been used for many decades, \nincluding for the treatment of chronic pain. However, \nnot all classes of medication are effective. We will fo-\ncus on tricyclics and dual selective antidepressants, \nwhich make up the group with the best results. (6) \nSelective serotonin reuptake inhibitors (SSRIs) have \nnot been consistently effective (7) and have shown \ninferior results than tricyclics. (8) For this reason, \nthey will not be included in this statement, but may \nbe considered in special situations by specialists \nin the field. Examples of these medications include \nparoxetine, fluoxetine, sertraline, citalopram and \nescitalopram.\nTricyclic antidepressants  \nDescription\nTricyclic antidepressants (TCAs) have been used for \ndecades to treat depression and various types of pain \n(off-label). These psychotropic drugs were launched \non the market in the 1960s. The best-known substanc-\nes are imipramine, amitriptyline, and nortriptyline, \nbut as the first has not shown uniform and robust re-\nsults in the treatment of chronic pain, we will focus \non the use of amitriptyline and nortriptyline.\nMechanisms of action\nTricyclic antidepressants exert their analgesic ef -\nfects through multiple mechanisms:\n1. Inhibition of serotonin and norepinephrine re-\nuptake, leading to increased synaptic levels of \nthese neurotransmitters, which are important in \nthe inhibitory modulation of pain perception;\n2. Blockade of sodium channels in peripheral \nnerves, reducing the transmission of pain sig-\nnals along nerve fibers. This characteristic is \nespecially relevant in the control of neuropathic \npain; and\n3. Modulation of the N-methyl-D-aspartate (NMDA) \nreceptor, which plays a role in CS and the percep-\ntion of chronic pain, which is attributed to the \npotential for controlling nociplastic pain.\nEfficacy in chronic pain\nNumerous clinical trials and observational studies \nhave demonstrated the efficacy of TCAs in the man-\nagement of chronic pain conditions. Currently, their \nmain application is in neuropathic pain and noci -\nplastic pain. This class is effective in the treatment \nof neuropathic pain, such as that associated with \ndiabetic neuropathy, postherpetic neuralgia, and \n\n3 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nPoli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al.\nperipheral neuropathy. (9) Conditions such as fibro-\nmyalgia and chronic pelvic pain are often associated \nwith a significant nociplastic component, and TCAs \nhave also shown to be effective in these conditions. \nNortriptyline is often preferred in these cases due to \nits favorable side effect profile. Despite its proven ef-\nfect, the Food and Drug Administration (FDA) has not \napproved the drug for the treatment of pain, meaning \nits use in the United States is off-label.\nDosage recommendations\nDue to the high prevalence of side effects and the \nconsequent difficulty in adherence, it is recommend-\ned to start with the lowest possible doses, followed by \na progressive and supervised increase. There is still a \ngap in the literature regarding the ideal dosage, du -\nration of treatment and long-term results associated \nwith the use of TCAs in pain management. Clinical \nimprovement is usually noticeable after one or two \nweeks of starting use. However, it can take an aver -\nage of six weeks or more to obtain a significant result \n(reduction of at least 30% in initial pain scores).\nBefore starting the prescription, the profession-\nal must bear in mind that the goal is to maintain the \nlowest possible effective dose. Based on this, the rec-\nommendations are as follows:\nAmitriptyline and nortriptyline: the starting dose \nshould be as low as possible (between 10-25 mg/day), \nfollowed by weekly or biweekly assessment with pro-\ngressive and additional increases of 25 mg/day. Once \nthe dose of 75-100 mg/day has been reached, main-\ntaining this for a longer period (approximately four \nweeks) is prudent before increasing further. The max-\nimum recommended dose of amitriptyline is 300 \nmg/day and that of nortriptyline is 150 mg/day. Doses \nabove 150 mg/day have been associated with little \nimprovement in the control of chronic pelvic pain. \nOnce the therapeutic dose has been established, we \nrecommend maintaining it for 6-12 months, depend -\ning on the individual progress of each patient and \nother pain control measures or coping mechanisms \nincorporated. Abrupt discontinuation of this medica-\ntion is strongly discouraged.\nSide effects\nAlthough TCAs can be effective in managing pain, \nthey are not free from side effects, which are mostly \ndue to their anticholinergic action, but not exclusive-\nly. The most common side effects include dry mouth, \nconstipation, sedation, weight gain, reduced sexual \ndesire, blurred vision, tremor, sweating, nausea and \ntachycardia. In older adults, TCAs may increase the \nrisk of falls and cognitive impairment. Less com-\nmon side effects include orthostatic hypotension, \narrhythmias, urinary retention, dry eyes, and memo-\nry problems. Therefore, careful patient selection and \nmonitoring are essential when using TCAs for pain \nmanagement.\nRisks and precautions\n1. Suicidal thoughts: as with many antidepressant \nmedications, some people, especially children, \nadolescents, and young adults, may experience \nan increase in suicidal thoughts or behaviors \nwhen taking TCAs. Close monitoring and regular \ncommunication with a healthcare professional \nare crucial during the first few weeks of treatment.\n2. Serotonin syndrome: this is characterized by \nanxiety, irritability, muscle twitching, confusion \nand hallucinations, tremors and chills, nausea \nand diarrhea, increased blood pressure and \nheart rate, increased reflexes, and dilated pupils. \nThe triggering may be associated not only with \nthe use of high doses, but also with the concom-\nitant use of other antidepressants, triptans for \nmigraine (e.g., sumatriptan), opioids (codeine, \ntramadol, meperidine, etc.), antiemetics (meto-\nclopramide, ondansetron), anticonvulsants \n(carbamazepine, valproic acid), erythromycin, \nciprofloxacin, fluconazole, ritonavir, cocaine, \namphetamines, LSD, ecstasy, tryptophan, St. \nJohn’s wort, and ginseng.(10)\n3. Withdrawal symptoms: abrupt discontinuation \nof TCAs may lead to withdrawal symptoms, in-\ncluding nausea, headache, and mood swings. \nGradually reducing the medication under the \nguidance of a healthcare professional may help \nmitigate the effects of withdrawal.\nDrug interactions\n1. Monoamine oxidase inhibitors (MAOIs): com-\nbining TCAs with MAOIs can lead to a potentially \nlife-threatening condition called serotonin syn-\ndrome. There must be a significant time interval \n(usually two weeks or more) between discontin-\nuing an MAOI and starting a TCA.\n2. Serotonin: combining TCAs with other serotoner-\ngic drugs, such as selective serotonin reuptake \ninhibitors (SSRIs) or serotonin-norepinephrine \nreuptake inhibitors (SNRIs), may increase the \nrisk of serotonin syndrome.\n3. Antipsychotics: some antipsychotic drugs, es-\npecially those with anticholinergic effects such \nas chlorpromazine, may interact with TCAs and \nsignificantly increase the risk of side effects.\n4. Anticholinergics: concomitant use with antihis-\ntamines or antiparkinsonian drugs may also in-\ncrease the risk of side effects.\n5. Antiarrhythmics: TCAs can affect cardiac con-\nduction, so combining them with certain antiar -\nrhythmic medications may increase the risk of \narrhythmias.\n\n4  FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nUse of oral neuromodulators in chronic pelvic pain\n6. Anticoagulants: there may be an increased risk \nof bleeding due to the antiplatelet activity of \nTCAs.\n7. Antihypertensives: TCAs may interact with some \nmedications in the beta-blocker, calcium chan-\nnel blocker, and clonidine classes, potential -\nly causing additive or antagonistic effects on \nblood pressure.\n8. Interactions with cytochrome P450 (CYP450) \nenzymes: TCAs may interact with the CYP450 \nenzyme system, potentially affecting the metab-\nolism of other medications.\nSelective serotonin and norepinephrine \nreuptake inhibitors\nDescription\nSelective serotonin and norepinephrine reuptake in-\nhibitors, also called “duals” , initially gained notoriety \nin the treatment of depression due to their excellent \nresults, coupled with a better side effect profile than \ntricyclics. Their recognition as a class of drugs with \nanalgesic properties is mainly due, but not only, to \ntheir effect as a modulator of norepinephrine re-\nuptake, which is essential in modulating pain in hu -\nmans. They have been on the world market since the \n1990s. The most widely known substances are: dulox-\netine, venlafaxine and desvenlafaxine.\nMechanisms of action\nSerotonin-norepinephrine reuptake inhibitors such \nas duloxetine and venlafaxine, modulate neurotrans-\nmitter levels in the brain and spinal cord through a \nmain mechanism, (11) the inhibition of serotonin and \nnorepinephrine reuptake in the synaptic cleft.\nEfficacy in chronic pain\nSerotonin-norepinephrine reuptake inhibitors have \ndemonstrated efficacy in the treatment of several \nchronic pain conditions, particularly those including \nneuropathic and nociplastic components such as fi -\nbromyalgia, diabetic neuropathy, peripheral neurop-\nathy, and chronic musculoskeletal pain. Duloxetine, \nin particular, is FDA-approved for these indications \nand is the only one with good evidence in the liter -\nature for significant pain reduction and proven im-\nprovement in quality of life in clinical trials.(12,13)\nDosage recommendations\nAlthough the side effect profile is slightly better com-\npared to the use of tricyclics, we recommend starting \nwith a low dose and gradually increasing it to reduce \nthe rate of adverse effects and, consequently, avoid \nloss of adherence. There is still a gap in the literature \nregarding optimal dosage, duration of treatment, and \nlong-term outcomes associated with the use of SNRIs \nin pain management. Clinical improvement may be \nnoticeable from the first 24 hours of use, but general-\nly after the first week. On average, it takes about 30-\n40 days to obtain a significant result (at least a 30% \nreduction in initial pain scores).\nBefore starting the prescription, the profession-\nal should keep in mind that the goal is to maintain \nthe lowest possible effective dose. Based on this, the \nrecommendations are as follows:\nDuloxetine: the starting dose should be as low as \npossible (about 20 mg/day), followed by a weekly as-\nsessment. Any dose increases should be progressive \nand, preferably, 20 mg/day each week. Once the dose \nof 60 mg/day is reached, maintaining this for a longer \nperiod (about 2-3 weeks) is prudent before further \nprogressions. The maximum recommended dose is \n120 mg/day. Doses higher than 60 mg/day have not \nshown significant additional benefits and safety has \nnot been adequately evaluated.\nVenlafaxine: the starting dose should be as low \nas possible (about 37.5 mg/day), followed by a weekly \nassessment. Any dose increases should be progres-\nsive and preferably 37.5 mg/day each week. Once the \ndose of 150 mg/day has been reached, maintaining \nthis for a longer period (approximately 2-3 weeks) is \nprudent before increasing further. Doses higher than \n225 mg/day are not usual to ensure efficacy. Doses \nhigher than 375 mg/day should not be prescribed.\nDesvenlafaxine: the usual starting dose is 50 mg/\nday. Progression should occur after two weeks, but \ndoses higher than 50 mg/day have not been shown to \nprovide additional benefits for pain control. More re-\ncently, the recommended treatment has been to start \nwith just 25 mg/day, with possible progression after \ntwo weeks. Doses higher than 400 mg/day should not \nbe prescribed.\nSide effects\nAlthough generally well tolerated, SNRIs can cause \nside effects, including nausea, headache, dizziness, \ndry mouth, drowsiness or insomnia, sedation, exces-\nsive sweating, reduced sexual desire, and difficulty \nachieving orgasm. Increased blood pressure is un-\ncommon, but is especially associated with the use \nof venlafaxine at higher doses. Regular monitoring \nof blood pressure may be necessary. Less commonly, \nit is associated with serotonin syndrome, which has \nbeen described previously.\nRisks and precautions\n1. Suicidal thoughts: some people, especially chil -\ndren, adolescents, and young adults, may expe-\nrience an increase in suicidal thoughts or be-\nhavior when taking SSRIs. Close monitoring and \nregular communication with a healthcare pro-\nfessional are crucial during the first few weeks \nof treatment.\n\n5 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nPoli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al.\n2. Risk of bleeding: SSRIs may increase the risk of \nbleeding, especially when combined with anti -\ncoagulant or antiplatelet medications. Use cau -\ntion if you are taking these medications at the \nsame time.\n3. Serotonin syndrome: this is less commonly seen \nand has been described previously. Patients \nshould be informed of the risk and instructed to \nrecognize the signs and symptoms.\n4. Withdrawal symptoms: Stopping SSRIs abruptly \ncan lead to withdrawal symptoms, such as diz -\nziness, nausea, headache, irritability, and mood \nswings. Gradually reducing the medication un-\nder the guidance of a healthcare professional \ncan help mitigate the effects of withdrawal.\nDrug interactions\n1. MAOIs: Combining SSRIs with MAOIs can lead to \nserotonin syndrome. There should be a signif -\nicant interval (usually two weeks or more) be-\ntween stopping an MAOI and starting an SSRI.\n2. Serotonin: combining SSRIs with other seroto-\nnergic medications, such as SSRIs or triptans \n(used for migraines), can also increase the risk \nof serotonin syndrome.\n3. Anticoagulants and antiplatelet agents: SSRIs \nmay increase the risk of bleeding when taken \nwith anticoagulant drugs, such as warfarin, or \nantiplatelet agents, such as aspirin.\n4. Antihypertensives: TCAs may interact with \nsome drugs in the beta-blocker, calcium chan-\nnel blocker and clonidine classes, which may \ncause additive or antagonistic effects on blood \npressure.\n5. CYP450 enzyme inhibitors: some drugs that in-\nhibit the CYP450 enzyme system may increase \nblood levels of SSRIs, which may lead to side ef -\nfects or toxicity.\nGabapentinoids – when and how to use them?\nDescription \nGabapentinoids are drugs in the anticonvulsant \nclass. They are analogues of gamma-aminobutyr -\nic acid (GABA), which is one of the main inhibitory \nneurotransmitters in the CNS. The substances that \nrepresent this class are gabapentin and pregabalin. \nAs mentioned, they were initially developed for the \ntreatment of epilepsy in the 1990s, but were quick -\nly incorporated as drugs for the treatment of pain \nat the beginning of the century, especially neuro-\npathic pain. There is currently extensive evidence \nto support its use as the first line of treatment for \nthis condition. (14,15) Despite being newer and having \nfewer studies in the literature, pregabalin appears \nto have the same efficacy. (16) It is important to em-\nphasize that its indiscriminate use without clear \ncriteria for the treatment of chronic pelvic pain in \nwomen is not supported by the literature. (17)\nMechanisms of action\nGabapentinoids exert their analgesic effects \nthrough the following mechanisms:(18)\n6. Inhibition of calcium channels: gabapentinoids \nbind primarily to the α2δ subunit of voltage-gat -\ned calcium channels in the CNS, reducing calci -\num entry into neurons. This action decreases the \nrelease of neurotransmitters and neuronal excit-\nability, contributing to pain modulation.\n7. GABAergic activity: gabapentinoids can in-\ncrease GABA neurotransmission, which can in-\nhibit excessive signaling in pain pathways.\nEfficacy in chronic pain\nClinical trials and real-world evidence support the \nuse of gabapentinoids in the management of chron-\nic pain conditions, including diabetic neuropathy, \npostherpetic neuralgia, and chronic low back pain. \nPregabalin is FDA-approved for these indications \nand has demonstrated efficacy in reducing pain and \nimproving quality of life.\nDosage recommendations\nThe side effect profile is better than that of antide-\npressants, but we also recommend starting with a \nlow dose and gradually increasing it to reduce the \nrate of side effects and, consequently, avoid loss \nof adherence. While gabapentin has a nonlinear \npharmacokinetic profile, pregabalin has a linear re-\nlationship between the dose used and the plasma \nconcentration. This particular pharmacodynamic \nfeature makes pregabalin more comfortable to use \n(twice a day, instead of three times a day as with ga -\nbapentin) and has effective results observed more \nquickly (after one day of use, compared to 9-10 for \ngabapentin). On average, it takes about 5-6 weeks to \nobtain a significant result (at least a 30% reduction \nin initial pain scores).\nBefore starting the prescription, the profession-\nal should keep in mind the goal to maintain the low-\nest possible effective dose. Based on this, the recom-\nmendations are as follows:\nGabapentin: the initial dose is 900 mg/day di -\nvided into three doses (three 300 mg tablets/day). It \nis usual to follow a progressive schedule: 300 mg on \nday one, 600 mg on day two, and 900 mg from day \nthree onwards. From then on, it is possible to prog-\nress in increments of 300 mg/day every 4-5 days \nup to a total dose of 1,800 mg/day. Data associated \nwith significant improvement above this dose are \nstill lacking. The dose should not exceed 3,600 mg/\nday. There are more conservative options for dose \nprogression, for example: 300 mg/day in week one, \n\n6  FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nUse of oral neuromodulators in chronic pelvic pain\n600 mg/day in week two, 900 mg/day in week three, \nfollowed by biweekly or even monthly increases up to \nthe total dose of 1,800 mg/day.\nPregabalin: the initial dose is 150 mg/day di -\nvided into two doses (two 75 mg tablets/day). It is \nusual to follow a progressive regimen: 75 mg on day \none, 150 mg on day two. From then on, it is possible \nto progress in increments of 75 mg/day every three \ndays up to a total dose of 450 mg/day. Data associ -\nated with significant improvement above this dose \nare lacking. The limit of 600 mg/day should not be ex-\nceeded. There are also more conservative options for \ndose progression, for example: 50-75 mg/day in week \none, 100-150 mg/day in week two, 150 mg/day in week \nthree, followed by weekly or even biweekly increases \nup to a total dose of 450 mg/day.\nSide effects\nAlthough gabapentinoids are generally well tolerat -\ned, they are not free from side effects. Common ad -\nverse effects include dizziness, drowsiness, periph-\neral edema, weight gain, dry mouth, nausea, blurred \nvision, and mood changes. Pregabalin is associated \nwith a lower risk of adverse effects compared with ga-\nbapentin due to its more predictable pharmacokinet-\nics. Gabapentinoids rarely cause serious side effects \nsuch as angioedema and respiratory depression, es-\npecially at high doses or when combined with other \nCNS depressants.\nRisks and precautions\n1. Suicidal thoughts: as with many drugs that af -\nfect the CNS, some people, especially children, \nadolescents, and young adults, may experience \nan increase in suicidal thoughts or behavior \nwhen taking gabapentinoids. Close monitoring \nand regular communication with a healthcare \nprofessional are important during the first few \nweeks of treatment.\n2. Withdrawal symptoms: abruptly stopping gab-\napentinoids may lead to withdrawal symptoms, \nincluding anxiety, insomnia, nausea, and sweat-\ning. Gradually reducing your medication under \nthe guidance of a healthcare professional may \nhelp mitigate the effects of withdrawal.\nDrug interactions\n1. Opioids: Combining gabapentinoids with opi -\noids, such as hydrocodone or oxycodone, may \nincrease the risk of respiratory depression and \noverdose. This combination has been associated \nwith an increased risk of opioid-related deaths.\n2. Alcohol and sedatives: combining gabapenti -\nnoids with alcohol or other CNS depressants \n(e.g., benzodiazepines) may increase sedation \nand impair cognitive and motor skills.\n3. Antacids: if taken simultaneously, antacids con-\ntaining aluminum or magnesium may reduce \nthe absorption of gabapentinoids. It is advisable \nto take these medications at least two hours \napart.\n4. Antiepileptic medications: Some antiepileptic \nmedications such as phenytoin or carbamaze-\npine may reduce the effectiveness of gabapenti-\nnoids and require dosage adjustments.\n5. CYP450 interactions: although gabapentinoids \nthemselves do not significantly interact with \nCYP450, other drugs that interact with CYP450 \nenzymes may affect gabapentinoid metabolism.\nCannabinoids – when and how to use them?\nDescription\nCannabinoids, both natural and synthetic, have been \ngaining attention for their potential analgesic effect \nin the treatment of chronic pain.(19,20) Although it may \nbe somewhat premature to include this class of drugs \nin this statement, it seems pertinent in view of the \ngreat demand observed in clinical practice and the \nwidespread use that has been perceived in the search \nfor the use of natural cannabis and products contain-\ning cannabinoids, as well as the increase in medi -\ncal prescriptions for this purpose. The International \nAssociation for the Study of Pain (IASP), one of the \nworld’s leading entities in the area of expertise, pub-\nlished a position statement in 2021(21) recognizing the \nlegitimacy of the life experience of people who report \nimprovement in their pain with the use of cannabis \nand cannabinoids, but making it clear that the entity \ndoes not endorse their use until rigorous investiga -\ntions and robust results clearly show the benefits and \nrisks of use in humans.\nMechanisms of action\nCannabinoids exert their analgesic effects through \nthe endocannabinoid system. Key mechanisms \ninclude:\n1. Cannabinoid receptor (CB1) activation: CB1 re-\nceptors in the CNS modulate pain perception by \ninhibiting the release of neurotransmitters in-\nvolved in pain signaling.\n2. CB2 receptor activation: CB2 receptors found \nprimarily in the immune system may reduce \ninflammation, which is often a component of \nchronic and neuropathic pain.\n3. Endocannabinoid release: cannabinoids may in-\ncrease the activity of endocannabinoids, such as \nanandamide and 2-arachidonoyl glycerol (2-AG), \nwhich play roles in pain modulation.\nEfficacy in chronic pain\nClinical trials and observational studies have shown \nmixed results regarding the efficacy of cannabinoids in \n\n7 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nPoli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al.\nthe management of chronic pain. Some people report \nsignificant pain relief, while others do not experience \nthe same benefits. Variability in individual responses \nand in the specific type and dose of cannabinoids used \nmay contribute to these discrepancies.(22)\nDosage recommendations\nCannabinoids are generally safe. (23) However, to \ndate, in the chronic pelvic pain world, there is no ro-\nbust literature to support this statement to recom-\nmend a defined dose or safety margin for the popu -\nlation. Use outside of controlled settings should be \ndiscouraged until sufficient data support their use. \nPractitioners and patients need to be aware that \nthere is evidence of the potential harmful effects \nof this class of medications for some individuals, \nparticularly adolescents and those with psychiatric \ndisorders.(24) Another important issue is the legal \nstatus of derivatives, which varies widely between \njurisdictions. Healthcare professionals should be \naware of local regulations and prescribe cannabi -\nnoids in accordance with the law. (25)\nSide effects\nThe use of cannabinoids is associated with sever -\nal side effects, including dizziness, dry mouth, in-\ncreased appetite, sedation, and cognitive impair -\nment, impairing coordination and reaction times. In \naddition, there are concerns about the potential for \ndependence and withdrawal. It is essential to consid-\ner the patient’s overall health, potential drug interac-\ntions, and individual response when using cannabi -\nnoids for pain management.\nRisks and precautions\n1. Psychosis and anxiety: In some individuals, es-\npecially those with a predisposition to psychi -\natric conditions, cannabinoids may trigger or \nworsen psychotic symptoms or anxiety.\n2. Paranoia: Some individuals may experience \nheightened feelings of paranoia or anxiety when \nusing cannabinoids.\n3. Impairment of memory and cognitive function: \nLong-term use of cannabinoids, especially at \nhigh doses, may affect memory, attention, and \ncognitive function.\n4. Cardiovascular effects: cannabinoids can cause \nchanges in heart rate and blood pressure, which \ncan be a concern for people with heart problems.\n5. Respiratory effects: smoking cannabis can lead \nto respiratory problems similar to those caused \nby tobacco, including chronic bronchitis and \nlung problems.\n6. Dependence: Long-term use of cannabinoids \ncan lead to physical and psychological depen-\ndence in some people.\n7. Withdrawal syndrome: stopping cannabinoids \nafter regular use can result in withdrawal symp-\ntoms, including irritability, insomnia, loss of ap-\npetite, and mood swings.\nDrug interactions\n1. Alcohol: Combining cannabinoids with alcohol \nmay increase the risk of drowsiness, impaired \ncoordination, and cognitive impairment.\n2. CNS depressants: Combining cannabinoids \nwith other CNS depressants, such as benzodi -\nazepines, opioids or sedative medications may \npotentiate the sedative effects and increase the \nrisk of respiratory depression.\n3. Anticoagulants: some cannabinoids, such as \nTHC, may interact with anticoagulants, poten-\ntially affecting their anticoagulant effects.\n4. CYP450 interactions: certain cannabinoids may \ninteract with the enzyme system. This may affect \nthe metabolism and efficacy of other medications.\n5. Antipsychotic medications: combining canna -\nbinoids with antipsychotic medications may \nresult in increased sedation and cognitive \nimpairment.\n6. MAOIs: combining cannabinoids with MAOIs \nmay result in unpredictable effects and is gener-\nally not recommended.\nFinal considerations\nBased on the best current evidence, we recommend \nthe following as first-line treatment for neuropathic \nand nociplastic pain, in order of priority:\nNeuropathic:\n1. Gabapentinoid\n2. Tricyclic antidepressant\n3. SNRI antidepressant\nNociplastic:\n1. SNRI antidepressant \n2. Gabapentinoid\n3. Tricyclic antidepressant\nReferences\n1. Siqueira-Campos VM, de Deus MS, Poli-Neto OB, Rosa-E-Silva JC, \nde Deus JM, Conde DM. Current challenges in the management \nof chronic pelvic pain in women: from bench to bedside. Int J \nWomens Health. 2022;14:225-44. doi: 10.2147/IJWH.S224891\n2. Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A. Nonsteroidal \nanti-inflammatory drugs for pain in women with endometriosis. \nCochrane Database Syst Rev. 2017;2017(1):CD004753. doi: \n10.1002/14651858.CD004753.pub4\n3. Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. \nCentral changes associated with chronic pelvic pain and \nendometriosis. Hum Reprod Update. 2014;20(5):737-47. doi: \n10.1093/humupd/dmu025\n4. Nijs J, Lahousse A, Kapreli E, Bilika P , Saraçoğlu İ, Malfliet \nA, et al. Nociplastic pain criteria or recognition of central \nsensitization? Pain phenotyping in the past, present and \nfuture. J Clin Med. 2021;10(15):3203. doi: 10.3390/jcm10153203\n\n8  FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nUse of oral neuromodulators in chronic pelvic pain\n5. Fitzcharles MA, Cohen SP , Clauw DJ, Littlejohn G, Usui C, \nHäuser W. Nociplastic pain: towards an understanding of \nprevalent pain conditions. Lancet. 2021;397(10289):2098-110. \ndoi: 10.1016/S0140-6736(21)00392-5\n6. Ferreira GE, Abdel-Shaheed C, Underwood M, Finnerup NB, \nDay RO, McLachlan A, et al. Efficacy, safety, and tolerability \nof antidepressants for pain in adults: overview of systematic \nreviews. BMJ. 2023;380:e072415. doi: 10.1136/bmj-2022-072415\n7. Patetsos E, Horjales-Araujo E. Treating chronic pain with ssris: \nwhat do we know? Pain Res Manag. 2016;2016:2020915. doi: \n10.1155/2016/2020915\n8. Bonilla-Jaime H, Sánchez-Salcedo JA, Estevez-Cabrera MM, Molina-\nJiménez T, Cortes-Altamirano JL, Alfaro-Rodríguez A. Depression \nand pain: use of antidepressants. Curr Neuropharmacol. \n2022;20(2):384-402. doi: 10.2174/1570159X19666210609161447\n9. Obata H. Analgesic mechanisms of antidepressants for \nneuropathic pain. Int J Mol Sci. 2017;18(11):2483. doi: 10.3390/\nijms18112483\n10. Scotton WJ, Hill LJ, Williams AC, Barnes NM. Serotonin \nsyndrome: pathophysiology, clinical features, management, \nand potential future directions. Int J Tryptophan Res. \n2019;12:1178646919873925. doi: 10.1177/1178646919873925\n11. Fanelli D, Weller G, Liu H. New serotonin-norepinephrine \nreuptake inhibitors and their anesthetic and analgesic \nconsiderations. Neurol Int.  2021;13(4):497-509. doi: 10.3390/\nneurolint13040049\n12. Birkinshaw H, Friedrich CM, Cole P , Eccleston C, Serfaty M, \nStewart G, et al. Antidepressants for pain management in \nadults with chronic pain: a network meta-analysis. Cochrane \nDatabase Syst Rev. 2023;5(5):CD014682. doi: 10.1002/14651858.\nCD014682.pub2\n13. Lian YN, Wang Y, Zhang Y, Yang CX. Duloxetine for pain \nin fibromyalgia in adults: a systematic review and a \nmeta-analysis. Int J Neurosci. 2020;130(1):71-82. doi: \n10.1080/00207454.2019.1664510\n14. Wiffen PJ, Derry S, Bell RF, Rice AS, Tölle TR, Phillips T, et al. \nGabapentin for chronic neuropathic pain in adults. Cochrane \nDatabase Syst Rev. 2017;6(6):CD007938. doi: 10.1002/14651858.\nCD007938.pub4\n15. Cavalli E, Mammana S, Nicoletti F, Bramanti P , Mazzon E. The \nneuropathic pain: an overview of the current treatment and \nfuture therapeutic approaches. Int J Immunopathol Pharmacol. \n2019;33:2058738419838383. doi: 10.1177/2058738419838383\n16. Derry S, Cording M, Wiffen PJ, Law S, Phillips T, Moore RA. \nPregabalin for pain in fibromyalgia in adults. Cochrane \nDatabase Syst Rev. 2016;(9):CD011790. doi: 10.1002/14651858.\nCD011790.pub2\n17. Horne AW, Vincent K, Hewitt CA, Middleton LJ, Koscielniak M, \nSzubert W, et al. Gabapentin for chronic pelvic pain in women \n(GaPP2): a multicentre, randomised, double-blind, placebo-\ncontrolled trial. Lancet. 2020;396(10255):909-17. doi: 10.1016/\nS0140-6736(20)31693-7\n18. Chincholkar M. Gabapentinoids: pharmacokinetics, \npharmacodynamics and considerations for clinical practice. \nBr J Pain. 2020;14(2):104-14. doi: 10.1177/2049463720912496\n19. Villanueva MR, Joshaghani N, Villa N, Badla O, Goit R, Saddik \nSE, et al. Efficacy, safety, and regulation of cannabidiol on \nchronic pain: a systematic review. Cureus. 2022;14(7):e26913. \ndoi: 10.7759/cureus.26913\n20. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. \nCannabis-based medicines for chronic neuropathic pain in \nadults. Cochrane Database Syst Rev. 2018;3:CD012182. doi: \n10.1002/14651858.CD012182.pub2\n21. IASP Presidential Task Force on Cannabis and Cannabinoid \nAnalgesia. International Association for the Study of Pain \nPresidential Task Force on Cannabis and Cannabinoid \nAnalgesia position statement. Pain.  2021;162 Suppl 1:S1-2. doi: \n10.1097/j.pain.0000000000002265\n22. McDonagh MS, Morasco BJ, Wagner J, Ahmed AY, Fu R, \nKansagara D, et al. Cannabis-based products for chronic pain: \na systematic review. Ann Intern Med. 2022;175(8):1143-53. doi: \n10.7326/M21-4520\n23. Sachs J, McGlade E, Yurgelun-Todd D. Safety and toxicology \nof cannabinoids. Neurotherapeutics. 2015;12(4):735-46. doi: \n10.1007/s13311-015-0380-8\n24. Hill KP , Gold MS, Nemeroff CB, McDonald W, Grzenda A, Widge \nAS, et al. Risks and benefits of cannabis and cannabinoids in \npsychiatry. Am J Psychiatry. 2022;179(2):98-109. doi: 10.1176/\nappi.ajp.2021.21030320\n25. Oliveira RA, Baptista AF, Sá KN, Barbosa LM, Nascimento \nOJ, Listik C, et al. Pharmacological treatment of central \nneuropathic pain: consensus of the Brazilian Academy \nof Neurology. Arq Neuropsiquiatr. 2020;78(11):741-52. doi: \n10.1590/0004-282X20200166\n\n9 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8.\nPoli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al.\nOmero Benedicto Poli Neto      \nDepartamento de Ginecologia e Obstetrícia, Faculdade de \nMedicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão \nPreto, SP , Brazil.\nJulio Cesar Rosa e Silva      \nDepartamento de Ginecologia e Obstetrícia, Faculdade de \nMedicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão \nPreto, SP , Brazil.\nCarlos Alberto Petta      \nUniversidade Estadual de Campinas, Campinas, SP , Brazil. Clínica \nFertilidade & Vida, Campinas, SP , Brazil. \nServiço de Reprodução Assistida, Hospital Sírio-Libanês, São \nPaulo, SP , Brazil.\nCarlos Augusto Pires Costa Lino      \nHospital Aliança, Salvador, BA, Brazil. \nInstituto de Perinatologia da Bahia, Salvador, BA, Brazil.\nEduardo Schor      \nEscola Paulista de Medicina, Universidade Federal de São Paulo, \nSão Paulo, SP , Brazil. \nHelizabet Salomão Abdalla Ayroza Ribeiro      \nFaculdade de Ciências Médicas, Santa Casa de São Paulo, São \nPaulo, SP , Brazil.\nJoão Nogueira Neto      \nUniversidade Federal do Maranhão, São Luís, MA, Brazil.\nJoão Sabino Lahorgue da Cunha Filho      \nDepartamento de Ginecologia e Obstetrícia, Universidade Federal \ndo Rio Grande do Sul, Porto Alegre, RS, Brazil.\nMarcia Cristina França      \nDepartamento de Ginecologia e Obstetrícia, Faculdade de \nMedicina, Universidade Federal de Minas Gerais, Belo Horizonte, \nMG, Brazil.\nMárcia Mendonça Carneiro      \nDepartamento de Ginecologia e Obstetrícia, Faculdade de Medicina, \nUniversidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.\nMarco Aurélio Pinho de Oliveira      \nFaculdade de Ciências Médicas, Universidade do Estado do Rio de \nJaneiro, Rio de Janeiro, RJ, Brazil.\nMarcos Tcherniakovsky      \nSetor de Videoendoscopia Ginecológica e Endometriose, \nFaculdade de Medicina do ABC, Santo André, SP , Brazil.\nMaurício Simões Abrão      \nDivisão de Ginecologia, Hospital Beneficência Portuguesa de São \nPaulo, São Paulo, SP , Brazil. \nDepartamento de Ginecologia e Obstetrícia, Faculdade de \nMedicina, Universidade de São Paulo, São Paulo, SP , Brazil.\nRaquel Papandreus Dib      \nUniversidade Federal de Ciências da Saúde de Porto Alegre, Porto \nAlegre, RS, Brazil.\nRicardo de Almeida Quintairos      \nNúcleo de Endometriose, Hospital Porto Dias, Belém, PA, Brazil.\nSergio Podgaec      \nDisciplina de Obstetrícia e Ginecologia, Faculdade de Medicina, \nUniversidade de São Paulo, São Paulo, SP , Brazil. \nHospital Israelita Albert Einstein, São Paulo, SP , Brazil.\nSidney Pearce      \nCentro Universitário Christus, Fortaleza, CE, Brazil.\nConflicts of interest:  \nNone to declare. \nHow to cite:  \nPoli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro \nHS, et al. Use of oral neuromodulators in chronic pelvic pain. Rev \nBras Ginecol Obstet. 2025;47:e-FPS8.\nNational Specialized Commission on Endometriosis of \nthe Brazilian Federation of Gynecology and Obstetrics \nAssociations (Febrasgo)\nPresident:\nRicardo de Almeida Quintairos \nVice-president:\nMárcia Mendonça Carneiro\nSecretary:\nCarlos Augusto Pires Costa Lino \nMembers:\nCarlos Alberto Petta\nEduardo Schor\nHelizabet Salomão Abdalla\nJoao Nogueira Neto\nJoão Sabino Lahorgue da Cunha Filho \nJulio Cesar Rosa e Silva\nMarcia Cristina França\nMarco Aurélio Pinho de Oliveira \nMarcos Tcherniakovsky\nMaurício Simões Abrão\nOmero Benedicto Poli Neto\nRaquel Papandreus Dib\nSergio Podgaec\nSidney Pearce","source_license":"CC0","license_restricted":false}