Use of oral neuromodulators in chronic pelvic painNumber 8 – 2025

Chronic pelvic pain is a common and complex condi- tion that can negatively affect people’s quality of life. Various associated diseases can lead to symptoms through diverse mechanisms. In clinical practice, in ad- dition to seeking a specific diagnosis, it is essential to typify the pain perceived by the patient. This is crucial in planning the therapeutic approach and consequent- ly, achieving better medium and long-term outcomes.(1) Pain can be simplified and classified as noci - ceptive (also known as inflammatory), neuropath- ic and nociplastic. Other categories can be listed, but are beyond the scope of this statement. In the first case, it is triggered predominantly by peripher - al mechanisms directly induced by the underlying disease(s). Thus, treating the underlying disease and using adjuvant analgesics from the non-steroi - dal anti-inflammatory drug (NSAID) class is gener - 2 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Use of oral neuromodulators in chronic pelvic pain ally effective for curing and/or controlling pain for a relatively long period. (2) In the case of neuropath- ic pain, the primary condition may also be directly responsible for the neurological impairment. Thus, its treatment often results in substantial improve- ment in pain, but neurological damage often per - sists and personalized adjuvant treatment must be instituted. In this case, NSAIDs are not effective and may even lead to an increase in the perception of pain. Gabapentinoids have proven to be the most effective drugs in relieving this symptom, but anti - depressants have excellent results that have been known for a long time. As should be evident from everyone’s clinical experience, specific treatment of these “prima - ry” diseases does not always result in the cure or prolonged control of painful symptoms. This is due, at least in part, to the involvement of the cen- tral nervous system (CNS) in the pathophysiology of chronic pain.(3) The pain resulting from this condition is called nociplastic and is triggered by changes in the CNS, the main one being central sensitization (CS). Briefly, CS is a process in which the individual becomes more sensitive to pain due to the reduction or loss of effectiveness of the inhibitory modulation system. Perhaps the most curious and particular thing about this condition is that it is the primary cause of the perpetuation of chronic pain. In other words, in this case, the painful symptom does not de- pend on a possible primary triggering cause. Even if it is completely eliminated, the symptoms persist. (4) The study of nociplastic pain has been the focus in the investigation of processes that trigger and main- tain chronic pain. Clinically, it has been associated with symptoms such as changes in mood, memory and sleep patterns, and fatigue.(5) The medications we will discuss in this state- ment are part of the arsenal we can use to provide symptomatic relief to patients and have the greatest scientific basis in the current literature. Before delving into a specific discussion on the topic, it is important to emphasize the vast and rap- idly expanding field of pain pathophysiology. It is es- sential that we have the curiosity and responsibility to always keep ourselves updated. It is also important to emphasize two additional points. The first is that we do not intend to exhaust the topic and/or pres- ent all the possibilities of adjuvant treatments. We only present considerations of the medications that have proven to be the most effective in controlling chronic pelvic pain, whether as adjuvant or first-line treatment, or that have had increasing media appeal. We will focus on three classes: antidepressants, gab- apentinoids and cannabinoids. The second point are the several types of non-drug treatments included in the therapeutic arsenal that play an important role in the lasting relief of symptoms. These modalities should not be underestimated and be used as adju - vant measures whenever possible. Antidepressants. When and how to use them? Antidepressants have been used for many decades, including for the treatment of chronic pain. However, not all classes of medication are effective. We will fo- cus on tricyclics and dual selective antidepressants, which make up the group with the best results. (6) Selective serotonin reuptake inhibitors (SSRIs) have not been consistently effective (7) and have shown inferior results than tricyclics. (8) For this reason, they will not be included in this statement, but may be considered in special situations by specialists in the field. Examples of these medications include paroxetine, fluoxetine, sertraline, citalopram and escitalopram. Tricyclic antidepressants Description Tricyclic antidepressants (TCAs) have been used for decades to treat depression and various types of pain (off-label). These psychotropic drugs were launched on the market in the 1960s. The best-known substanc- es are imipramine, amitriptyline, and nortriptyline, but as the first has not shown uniform and robust re- sults in the treatment of chronic pain, we will focus on the use of amitriptyline and nortriptyline. Mechanisms of action Tricyclic antidepressants exert their analgesic ef - fects through multiple mechanisms: 1. Inhibition of serotonin and norepinephrine re- uptake, leading to increased synaptic levels of these neurotransmitters, which are important in the inhibitory modulation of pain perception; 2. Blockade of sodium channels in peripheral nerves, reducing the transmission of pain sig- nals along nerve fibers. This characteristic is especially relevant in the control of neuropathic pain; and 3. Modulation of the N-methyl-D-aspartate (NMDA) receptor, which plays a role in CS and the percep- tion of chronic pain, which is attributed to the potential for controlling nociplastic pain. Efficacy in chronic pain Numerous clinical trials and observational studies have demonstrated the efficacy of TCAs in the man- agement of chronic pain conditions. Currently, their main application is in neuropathic pain and noci - plastic pain. This class is effective in the treatment of neuropathic pain, such as that associated with diabetic neuropathy, postherpetic neuralgia, and 3 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Poli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al. peripheral neuropathy. (9) Conditions such as fibro- myalgia and chronic pelvic pain are often associated with a significant nociplastic component, and TCAs have also shown to be effective in these conditions. Nortriptyline is often preferred in these cases due to its favorable side effect profile. Despite its proven ef- fect, the Food and Drug Administration (FDA) has not approved the drug for the treatment of pain, meaning its use in the United States is off-label. Dosage recommendations Due to the high prevalence of side effects and the consequent difficulty in adherence, it is recommend- ed to start with the lowest possible doses, followed by a progressive and supervised increase. There is still a gap in the literature regarding the ideal dosage, du - ration of treatment and long-term results associated with the use of TCAs in pain management. Clinical improvement is usually noticeable after one or two weeks of starting use. However, it can take an aver - age of six weeks or more to obtain a significant result (reduction of at least 30% in initial pain scores). Before starting the prescription, the profession- al must bear in mind that the goal is to maintain the lowest possible effective dose. Based on this, the rec- ommendations are as follows: Amitriptyline and nortriptyline: the starting dose should be as low as possible (between 10-25 mg/day), followed by weekly or biweekly assessment with pro- gressive and additional increases of 25 mg/day. Once the dose of 75-100 mg/day has been reached, main- taining this for a longer period (approximately four weeks) is prudent before increasing further. The max- imum recommended dose of amitriptyline is 300 mg/day and that of nortriptyline is 150 mg/day. Doses above 150 mg/day have been associated with little improvement in the control of chronic pelvic pain. Once the therapeutic dose has been established, we recommend maintaining it for 6-12 months, depend - ing on the individual progress of each patient and other pain control measures or coping mechanisms incorporated. Abrupt discontinuation of this medica- tion is strongly discouraged. Side effects Although TCAs can be effective in managing pain, they are not free from side effects, which are mostly due to their anticholinergic action, but not exclusive- ly. The most common side effects include dry mouth, constipation, sedation, weight gain, reduced sexual desire, blurred vision, tremor, sweating, nausea and tachycardia. In older adults, TCAs may increase the risk of falls and cognitive impairment. Less com- mon side effects include orthostatic hypotension, arrhythmias, urinary retention, dry eyes, and memo- ry problems. Therefore, careful patient selection and monitoring are essential when using TCAs for pain management. Risks and precautions 1. Suicidal thoughts: as with many antidepressant medications, some people, especially children, adolescents, and young adults, may experience an increase in suicidal thoughts or behaviors when taking TCAs. Close monitoring and regular communication with a healthcare professional are crucial during the first few weeks of treatment. 2. Serotonin syndrome: this is characterized by anxiety, irritability, muscle twitching, confusion and hallucinations, tremors and chills, nausea and diarrhea, increased blood pressure and heart rate, increased reflexes, and dilated pupils. The triggering may be associated not only with the use of high doses, but also with the concom- itant use of other antidepressants, triptans for migraine (e.g., sumatriptan), opioids (codeine, tramadol, meperidine, etc.), antiemetics (meto- clopramide, ondansetron), anticonvulsants (carbamazepine, valproic acid), erythromycin, ciprofloxacin, fluconazole, ritonavir, cocaine, amphetamines, LSD, ecstasy, tryptophan, St. John’s wort, and ginseng.(10) 3. Withdrawal symptoms: abrupt discontinuation of TCAs may lead to withdrawal symptoms, in- cluding nausea, headache, and mood swings. Gradually reducing the medication under the guidance of a healthcare professional may help mitigate the effects of withdrawal. Drug interactions 1. Monoamine oxidase inhibitors (MAOIs): com- bining TCAs with MAOIs can lead to a potentially life-threatening condition called serotonin syn- drome. There must be a significant time interval (usually two weeks or more) between discontin- uing an MAOI and starting a TCA. 2. Serotonin: combining TCAs with other serotoner- gic drugs, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), may increase the risk of serotonin syndrome. 3. Antipsychotics: some antipsychotic drugs, es- pecially those with anticholinergic effects such as chlorpromazine, may interact with TCAs and significantly increase the risk of side effects. 4. Anticholinergics: concomitant use with antihis- tamines or antiparkinsonian drugs may also in- crease the risk of side effects. 5. Antiarrhythmics: TCAs can affect cardiac con- duction, so combining them with certain antiar - rhythmic medications may increase the risk of arrhythmias. 4 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Use of oral neuromodulators in chronic pelvic pain 6. Anticoagulants: there may be an increased risk of bleeding due to the antiplatelet activity of TCAs. 7. Antihypertensives: TCAs may interact with some medications in the beta-blocker, calcium chan- nel blocker, and clonidine classes, potential - ly causing additive or antagonistic effects on blood pressure. 8. Interactions with cytochrome P450 (CYP450) enzymes: TCAs may interact with the CYP450 enzyme system, potentially affecting the metab- olism of other medications. Selective serotonin and norepinephrine reuptake inhibitors Description Selective serotonin and norepinephrine reuptake in- hibitors, also called “duals” , initially gained notoriety in the treatment of depression due to their excellent results, coupled with a better side effect profile than tricyclics. Their recognition as a class of drugs with analgesic properties is mainly due, but not only, to their effect as a modulator of norepinephrine re- uptake, which is essential in modulating pain in hu - mans. They have been on the world market since the 1990s. The most widely known substances are: dulox- etine, venlafaxine and desvenlafaxine. Mechanisms of action Serotonin-norepinephrine reuptake inhibitors such as duloxetine and venlafaxine, modulate neurotrans- mitter levels in the brain and spinal cord through a main mechanism, (11) the inhibition of serotonin and norepinephrine reuptake in the synaptic cleft. Efficacy in chronic pain Serotonin-norepinephrine reuptake inhibitors have demonstrated efficacy in the treatment of several chronic pain conditions, particularly those including neuropathic and nociplastic components such as fi - bromyalgia, diabetic neuropathy, peripheral neurop- athy, and chronic musculoskeletal pain. Duloxetine, in particular, is FDA-approved for these indications and is the only one with good evidence in the liter - ature for significant pain reduction and proven im- provement in quality of life in clinical trials.(12,13) Dosage recommendations Although the side effect profile is slightly better com- pared to the use of tricyclics, we recommend starting with a low dose and gradually increasing it to reduce the rate of adverse effects and, consequently, avoid loss of adherence. There is still a gap in the literature regarding optimal dosage, duration of treatment, and long-term outcomes associated with the use of SNRIs in pain management. Clinical improvement may be noticeable from the first 24 hours of use, but general- ly after the first week. On average, it takes about 30- 40 days to obtain a significant result (at least a 30% reduction in initial pain scores). Before starting the prescription, the profession- al should keep in mind that the goal is to maintain the lowest possible effective dose. Based on this, the recommendations are as follows: Duloxetine: the starting dose should be as low as possible (about 20 mg/day), followed by a weekly as- sessment. Any dose increases should be progressive and, preferably, 20 mg/day each week. Once the dose of 60 mg/day is reached, maintaining this for a longer period (about 2-3 weeks) is prudent before further progressions. The maximum recommended dose is 120 mg/day. Doses higher than 60 mg/day have not shown significant additional benefits and safety has not been adequately evaluated. Venlafaxine: the starting dose should be as low as possible (about 37.5 mg/day), followed by a weekly assessment. Any dose increases should be progres- sive and preferably 37.5 mg/day each week. Once the dose of 150 mg/day has been reached, maintaining this for a longer period (approximately 2-3 weeks) is prudent before increasing further. Doses higher than 225 mg/day are not usual to ensure efficacy. Doses higher than 375 mg/day should not be prescribed. Desvenlafaxine: the usual starting dose is 50 mg/ day. Progression should occur after two weeks, but doses higher than 50 mg/day have not been shown to provide additional benefits for pain control. More re- cently, the recommended treatment has been to start with just 25 mg/day, with possible progression after two weeks. Doses higher than 400 mg/day should not be prescribed. Side effects Although generally well tolerated, SNRIs can cause side effects, including nausea, headache, dizziness, dry mouth, drowsiness or insomnia, sedation, exces- sive sweating, reduced sexual desire, and difficulty achieving orgasm. Increased blood pressure is un- common, but is especially associated with the use of venlafaxine at higher doses. Regular monitoring of blood pressure may be necessary. Less commonly, it is associated with serotonin syndrome, which has been described previously. Risks and precautions 1. Suicidal thoughts: some people, especially chil - dren, adolescents, and young adults, may expe- rience an increase in suicidal thoughts or be- havior when taking SSRIs. Close monitoring and regular communication with a healthcare pro- fessional are crucial during the first few weeks of treatment. 5 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Poli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al. 2. Risk of bleeding: SSRIs may increase the risk of bleeding, especially when combined with anti - coagulant or antiplatelet medications. Use cau - tion if you are taking these medications at the same time. 3. Serotonin syndrome: this is less commonly seen and has been described previously. Patients should be informed of the risk and instructed to recognize the signs and symptoms. 4. Withdrawal symptoms: Stopping SSRIs abruptly can lead to withdrawal symptoms, such as diz - ziness, nausea, headache, irritability, and mood swings. Gradually reducing the medication un- der the guidance of a healthcare professional can help mitigate the effects of withdrawal. Drug interactions 1. MAOIs: Combining SSRIs with MAOIs can lead to serotonin syndrome. There should be a signif - icant interval (usually two weeks or more) be- tween stopping an MAOI and starting an SSRI. 2. Serotonin: combining SSRIs with other seroto- nergic medications, such as SSRIs or triptans (used for migraines), can also increase the risk of serotonin syndrome. 3. Anticoagulants and antiplatelet agents: SSRIs may increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin, or antiplatelet agents, such as aspirin. 4. Antihypertensives: TCAs may interact with some drugs in the beta-blocker, calcium chan- nel blocker and clonidine classes, which may cause additive or antagonistic effects on blood pressure. 5. CYP450 enzyme inhibitors: some drugs that in- hibit the CYP450 enzyme system may increase blood levels of SSRIs, which may lead to side ef - fects or toxicity. Gabapentinoids – when and how to use them? Description Gabapentinoids are drugs in the anticonvulsant class. They are analogues of gamma-aminobutyr - ic acid (GABA), which is one of the main inhibitory neurotransmitters in the CNS. The substances that represent this class are gabapentin and pregabalin. As mentioned, they were initially developed for the treatment of epilepsy in the 1990s, but were quick - ly incorporated as drugs for the treatment of pain at the beginning of the century, especially neuro- pathic pain. There is currently extensive evidence to support its use as the first line of treatment for this condition. (14,15) Despite being newer and having fewer studies in the literature, pregabalin appears to have the same efficacy. (16) It is important to em- phasize that its indiscriminate use without clear criteria for the treatment of chronic pelvic pain in women is not supported by the literature. (17) Mechanisms of action Gabapentinoids exert their analgesic effects through the following mechanisms:(18) 6. Inhibition of calcium channels: gabapentinoids bind primarily to the α2δ subunit of voltage-gat - ed calcium channels in the CNS, reducing calci - um entry into neurons. This action decreases the release of neurotransmitters and neuronal excit- ability, contributing to pain modulation. 7. GABAergic activity: gabapentinoids can in- crease GABA neurotransmission, which can in- hibit excessive signaling in pain pathways. Efficacy in chronic pain Clinical trials and real-world evidence support the use of gabapentinoids in the management of chron- ic pain conditions, including diabetic neuropathy, postherpetic neuralgia, and chronic low back pain. Pregabalin is FDA-approved for these indications and has demonstrated efficacy in reducing pain and improving quality of life. Dosage recommendations The side effect profile is better than that of antide- pressants, but we also recommend starting with a low dose and gradually increasing it to reduce the rate of side effects and, consequently, avoid loss of adherence. While gabapentin has a nonlinear pharmacokinetic profile, pregabalin has a linear re- lationship between the dose used and the plasma concentration. This particular pharmacodynamic feature makes pregabalin more comfortable to use (twice a day, instead of three times a day as with ga - bapentin) and has effective results observed more quickly (after one day of use, compared to 9-10 for gabapentin). On average, it takes about 5-6 weeks to obtain a significant result (at least a 30% reduction in initial pain scores). Before starting the prescription, the profession- al should keep in mind the goal to maintain the low- est possible effective dose. Based on this, the recom- mendations are as follows: Gabapentin: the initial dose is 900 mg/day di - vided into three doses (three 300 mg tablets/day). It is usual to follow a progressive schedule: 300 mg on day one, 600 mg on day two, and 900 mg from day three onwards. From then on, it is possible to prog- ress in increments of 300 mg/day every 4-5 days up to a total dose of 1,800 mg/day. Data associated with significant improvement above this dose are still lacking. The dose should not exceed 3,600 mg/ day. There are more conservative options for dose progression, for example: 300 mg/day in week one, 6 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Use of oral neuromodulators in chronic pelvic pain 600 mg/day in week two, 900 mg/day in week three, followed by biweekly or even monthly increases up to the total dose of 1,800 mg/day. Pregabalin: the initial dose is 150 mg/day di - vided into two doses (two 75 mg tablets/day). It is usual to follow a progressive regimen: 75 mg on day one, 150 mg on day two. From then on, it is possible to progress in increments of 75 mg/day every three days up to a total dose of 450 mg/day. Data associ - ated with significant improvement above this dose are lacking. The limit of 600 mg/day should not be ex- ceeded. There are also more conservative options for dose progression, for example: 50-75 mg/day in week one, 100-150 mg/day in week two, 150 mg/day in week three, followed by weekly or even biweekly increases up to a total dose of 450 mg/day. Side effects Although gabapentinoids are generally well tolerat - ed, they are not free from side effects. Common ad - verse effects include dizziness, drowsiness, periph- eral edema, weight gain, dry mouth, nausea, blurred vision, and mood changes. Pregabalin is associated with a lower risk of adverse effects compared with ga- bapentin due to its more predictable pharmacokinet- ics. Gabapentinoids rarely cause serious side effects such as angioedema and respiratory depression, es- pecially at high doses or when combined with other CNS depressants. Risks and precautions 1. Suicidal thoughts: as with many drugs that af - fect the CNS, some people, especially children, adolescents, and young adults, may experience an increase in suicidal thoughts or behavior when taking gabapentinoids. Close monitoring and regular communication with a healthcare professional are important during the first few weeks of treatment. 2. Withdrawal symptoms: abruptly stopping gab- apentinoids may lead to withdrawal symptoms, including anxiety, insomnia, nausea, and sweat- ing. Gradually reducing your medication under the guidance of a healthcare professional may help mitigate the effects of withdrawal. Drug interactions 1. Opioids: Combining gabapentinoids with opi - oids, such as hydrocodone or oxycodone, may increase the risk of respiratory depression and overdose. This combination has been associated with an increased risk of opioid-related deaths. 2. Alcohol and sedatives: combining gabapenti - noids with alcohol or other CNS depressants (e.g., benzodiazepines) may increase sedation and impair cognitive and motor skills. 3. Antacids: if taken simultaneously, antacids con- taining aluminum or magnesium may reduce the absorption of gabapentinoids. It is advisable to take these medications at least two hours apart. 4. Antiepileptic medications: Some antiepileptic medications such as phenytoin or carbamaze- pine may reduce the effectiveness of gabapenti- noids and require dosage adjustments. 5. CYP450 interactions: although gabapentinoids themselves do not significantly interact with CYP450, other drugs that interact with CYP450 enzymes may affect gabapentinoid metabolism. Cannabinoids – when and how to use them? Description Cannabinoids, both natural and synthetic, have been gaining attention for their potential analgesic effect in the treatment of chronic pain.(19,20) Although it may be somewhat premature to include this class of drugs in this statement, it seems pertinent in view of the great demand observed in clinical practice and the widespread use that has been perceived in the search for the use of natural cannabis and products contain- ing cannabinoids, as well as the increase in medi - cal prescriptions for this purpose. The International Association for the Study of Pain (IASP), one of the world’s leading entities in the area of expertise, pub- lished a position statement in 2021(21) recognizing the legitimacy of the life experience of people who report improvement in their pain with the use of cannabis and cannabinoids, but making it clear that the entity does not endorse their use until rigorous investiga - tions and robust results clearly show the benefits and risks of use in humans. Mechanisms of action Cannabinoids exert their analgesic effects through the endocannabinoid system. Key mechanisms include: 1. Cannabinoid receptor (CB1) activation: CB1 re- ceptors in the CNS modulate pain perception by inhibiting the release of neurotransmitters in- volved in pain signaling. 2. CB2 receptor activation: CB2 receptors found primarily in the immune system may reduce inflammation, which is often a component of chronic and neuropathic pain. 3. Endocannabinoid release: cannabinoids may in- crease the activity of endocannabinoids, such as anandamide and 2-arachidonoyl glycerol (2-AG), which play roles in pain modulation. Efficacy in chronic pain Clinical trials and observational studies have shown mixed results regarding the efficacy of cannabinoids in 7 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Poli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al. the management of chronic pain. Some people report significant pain relief, while others do not experience the same benefits. Variability in individual responses and in the specific type and dose of cannabinoids used may contribute to these discrepancies.(22) Dosage recommendations Cannabinoids are generally safe. (23) However, to date, in the chronic pelvic pain world, there is no ro- bust literature to support this statement to recom- mend a defined dose or safety margin for the popu - lation. Use outside of controlled settings should be discouraged until sufficient data support their use. Practitioners and patients need to be aware that there is evidence of the potential harmful effects of this class of medications for some individuals, particularly adolescents and those with psychiatric disorders.(24) Another important issue is the legal status of derivatives, which varies widely between jurisdictions. Healthcare professionals should be aware of local regulations and prescribe cannabi - noids in accordance with the law. (25) Side effects The use of cannabinoids is associated with sever - al side effects, including dizziness, dry mouth, in- creased appetite, sedation, and cognitive impair - ment, impairing coordination and reaction times. In addition, there are concerns about the potential for dependence and withdrawal. It is essential to consid- er the patient’s overall health, potential drug interac- tions, and individual response when using cannabi - noids for pain management. Risks and precautions 1. Psychosis and anxiety: In some individuals, es- pecially those with a predisposition to psychi - atric conditions, cannabinoids may trigger or worsen psychotic symptoms or anxiety. 2. Paranoia: Some individuals may experience heightened feelings of paranoia or anxiety when using cannabinoids. 3. Impairment of memory and cognitive function: Long-term use of cannabinoids, especially at high doses, may affect memory, attention, and cognitive function. 4. Cardiovascular effects: cannabinoids can cause changes in heart rate and blood pressure, which can be a concern for people with heart problems. 5. Respiratory effects: smoking cannabis can lead to respiratory problems similar to those caused by tobacco, including chronic bronchitis and lung problems. 6. Dependence: Long-term use of cannabinoids can lead to physical and psychological depen- dence in some people. 7. Withdrawal syndrome: stopping cannabinoids after regular use can result in withdrawal symp- toms, including irritability, insomnia, loss of ap- petite, and mood swings. Drug interactions 1. Alcohol: Combining cannabinoids with alcohol may increase the risk of drowsiness, impaired coordination, and cognitive impairment. 2. CNS depressants: Combining cannabinoids with other CNS depressants, such as benzodi - azepines, opioids or sedative medications may potentiate the sedative effects and increase the risk of respiratory depression. 3. Anticoagulants: some cannabinoids, such as THC, may interact with anticoagulants, poten- tially affecting their anticoagulant effects. 4. CYP450 interactions: certain cannabinoids may interact with the enzyme system. This may affect the metabolism and efficacy of other medications. 5. Antipsychotic medications: combining canna - binoids with antipsychotic medications may

in increased sedation and cognitive impairment. 6. MAOIs: combining cannabinoids with MAOIs may result in unpredictable effects and is gener- ally not recommended. Final considerations Based on the best current evidence, we recommend the following as first-line treatment for neuropathic and nociplastic pain, in order of priority: Neuropathic: 1. Gabapentinoid 2. Tricyclic antidepressant 3. SNRI antidepressant Nociplastic: 1. SNRI antidepressant 2. Gabapentinoid 3. Tricyclic antidepressant

1. Siqueira-Campos VM, de Deus MS, Poli-Neto OB, Rosa-E-Silva JC, de Deus JM, Conde DM. Current challenges in the management of chronic pelvic pain in women: from bench to bedside. Int J Womens Health. 2022;14:225-44. doi: 10.2147/IJWH.S224891 2. Brown J, Crawford TJ, Allen C, Hopewell S, Prentice A. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2017;2017(1):CD004753. doi: 10.1002/14651858.CD004753.pub4 3. Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014;20(5):737-47. doi: 10.1093/humupd/dmu025 4. Nijs J, Lahousse A, Kapreli E, Bilika P , Saraçoğlu İ, Malfliet A, et al. Nociplastic pain criteria or recognition of central sensitization? Pain phenotyping in the past, present and future. J Clin Med. 2021;10(15):3203. doi: 10.3390/jcm10153203 8 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Use of oral neuromodulators in chronic pelvic pain 5. Fitzcharles MA, Cohen SP , Clauw DJ, Littlejohn G, Usui C, Häuser W. Nociplastic pain: towards an understanding of prevalent pain conditions. Lancet. 2021;397(10289):2098-110. doi: 10.1016/S0140-6736(21)00392-5 6. Ferreira GE, Abdel-Shaheed C, Underwood M, Finnerup NB, Day RO, McLachlan A, et al. Efficacy, safety, and tolerability of antidepressants for pain in adults: overview of systematic reviews. BMJ. 2023;380:e072415. doi: 10.1136/bmj-2022-072415 7. Patetsos E, Horjales-Araujo E. Treating chronic pain with ssris: what do we know? Pain Res Manag. 2016;2016:2020915. doi: 10.1155/2016/2020915 8. Bonilla-Jaime H, Sánchez-Salcedo JA, Estevez-Cabrera MM, Molina- Jiménez T, Cortes-Altamirano JL, Alfaro-Rodríguez A. Depression and pain: use of antidepressants. Curr Neuropharmacol. 2022;20(2):384-402. doi: 10.2174/1570159X19666210609161447 9. Obata H. Analgesic mechanisms of antidepressants for neuropathic pain. Int J Mol Sci. 2017;18(11):2483. doi: 10.3390/ ijms18112483 10. Scotton WJ, Hill LJ, Williams AC, Barnes NM. Serotonin syndrome: pathophysiology, clinical features, management, and potential future directions. Int J Tryptophan Res. 2019;12:1178646919873925. doi: 10.1177/1178646919873925 11. Fanelli D, Weller G, Liu H. New serotonin-norepinephrine reuptake inhibitors and their anesthetic and analgesic considerations. Neurol Int. 2021;13(4):497-509. doi: 10.3390/ neurolint13040049 12. Birkinshaw H, Friedrich CM, Cole P , Eccleston C, Serfaty M, Stewart G, et al. Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Cochrane Database Syst Rev. 2023;5(5):CD014682. doi: 10.1002/14651858. CD014682.pub2 13. Lian YN, Wang Y, Zhang Y, Yang CX. Duloxetine for pain in fibromyalgia in adults: a systematic review and a meta-analysis. Int J Neurosci. 2020;130(1):71-82. doi: 10.1080/00207454.2019.1664510 14. Wiffen PJ, Derry S, Bell RF, Rice AS, Tölle TR, Phillips T, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD007938. doi: 10.1002/14651858. CD007938.pub4 15. Cavalli E, Mammana S, Nicoletti F, Bramanti P , Mazzon E. The neuropathic pain: an overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol. 2019;33:2058738419838383. doi: 10.1177/2058738419838383 16. Derry S, Cording M, Wiffen PJ, Law S, Phillips T, Moore RA. Pregabalin for pain in fibromyalgia in adults. Cochrane Database Syst Rev. 2016;(9):CD011790. doi: 10.1002/14651858. CD011790.pub2 17. Horne AW, Vincent K, Hewitt CA, Middleton LJ, Koscielniak M, Szubert W, et al. Gabapentin for chronic pelvic pain in women (GaPP2): a multicentre, randomised, double-blind, placebo- controlled trial. Lancet. 2020;396(10255):909-17. doi: 10.1016/ S0140-6736(20)31693-7 18. Chincholkar M. Gabapentinoids: pharmacokinetics, pharmacodynamics and considerations for clinical practice. Br J Pain. 2020;14(2):104-14. doi: 10.1177/2049463720912496 19. Villanueva MR, Joshaghani N, Villa N, Badla O, Goit R, Saddik SE, et al. Efficacy, safety, and regulation of cannabidiol on chronic pain: a systematic review. Cureus. 2022;14(7):e26913. doi: 10.7759/cureus.26913 20. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3:CD012182. doi: 10.1002/14651858.CD012182.pub2 21. IASP Presidential Task Force on Cannabis and Cannabinoid Analgesia. International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia position statement. Pain. 2021;162 Suppl 1:S1-2. doi: 10.1097/j.pain.0000000000002265 22. McDonagh MS, Morasco BJ, Wagner J, Ahmed AY, Fu R, Kansagara D, et al. Cannabis-based products for chronic pain: a systematic review. Ann Intern Med. 2022;175(8):1143-53. doi: 10.7326/M21-4520 23. Sachs J, McGlade E, Yurgelun-Todd D. Safety and toxicology of cannabinoids. Neurotherapeutics. 2015;12(4):735-46. doi: 10.1007/s13311-015-0380-8 24. Hill KP , Gold MS, Nemeroff CB, McDonald W, Grzenda A, Widge AS, et al. Risks and benefits of cannabis and cannabinoids in psychiatry. Am J Psychiatry. 2022;179(2):98-109. doi: 10.1176/ appi.ajp.2021.21030320 25. Oliveira RA, Baptista AF, Sá KN, Barbosa LM, Nascimento OJ, Listik C, et al. Pharmacological treatment of central neuropathic pain: consensus of the Brazilian Academy of Neurology. Arq Neuropsiquiatr. 2020;78(11):741-52. doi: 10.1590/0004-282X20200166 9 FEBRASGO POSITION STATEMENT Rev Bras Ginecol Obstet. 2025;47:e-FPS8. Poli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al. Omero Benedicto Poli Neto Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP , Brazil. Julio Cesar Rosa e Silva Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP , Brazil. Carlos Alberto Petta Universidade Estadual de Campinas, Campinas, SP , Brazil. Clínica Fertilidade & Vida, Campinas, SP , Brazil. Serviço de Reprodução Assistida, Hospital Sírio-Libanês, São Paulo, SP , Brazil. Carlos Augusto Pires Costa Lino Hospital Aliança, Salvador, BA, Brazil. Instituto de Perinatologia da Bahia, Salvador, BA, Brazil. Eduardo Schor Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP , Brazil. Helizabet Salomão Abdalla Ayroza Ribeiro Faculdade de Ciências Médicas, Santa Casa de São Paulo, São Paulo, SP , Brazil. João Nogueira Neto Universidade Federal do Maranhão, São Luís, MA, Brazil. João Sabino Lahorgue da Cunha Filho Departamento de Ginecologia e Obstetrícia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Marcia Cristina França Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Márcia Mendonça Carneiro Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Marco Aurélio Pinho de Oliveira Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil. Marcos Tcherniakovsky Setor de Videoendoscopia Ginecológica e Endometriose, Faculdade de Medicina do ABC, Santo André, SP , Brazil. Maurício Simões Abrão Divisão de Ginecologia, Hospital Beneficência Portuguesa de São Paulo, São Paulo, SP , Brazil. Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP , Brazil. Raquel Papandreus Dib Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil. Ricardo de Almeida Quintairos Núcleo de Endometriose, Hospital Porto Dias, Belém, PA, Brazil. Sergio Podgaec Disciplina de Obstetrícia e Ginecologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP , Brazil. Hospital Israelita Albert Einstein, São Paulo, SP , Brazil. Sidney Pearce Centro Universitário Christus, Fortaleza, CE, Brazil. Conflicts of interest: None to declare. How to cite: Poli Neto OB, Rosa e Silva JC, Petta CA, Lino CA, Schor E, Ribeiro HS, et al. Use of oral neuromodulators in chronic pelvic pain. Rev Bras Ginecol Obstet. 2025;47:e-FPS8. National Specialized Commission on Endometriosis of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) President: Ricardo de Almeida Quintairos Vice-president: Márcia Mendonça Carneiro Secretary: Carlos Augusto Pires Costa Lino Members: Carlos Alberto Petta Eduardo Schor Helizabet Salomão Abdalla Joao Nogueira Neto João Sabino Lahorgue da Cunha Filho Julio Cesar Rosa e Silva Marcia Cristina França Marco Aurélio Pinho de Oliveira Marcos Tcherniakovsky Maurício Simões Abrão Omero Benedicto Poli Neto Raquel Papandreus Dib Sergio Podgaec Sidney Pearce