iCareBetter

Pain Medications

Medications are used to help alleviate the symptoms of endometriosis. They do not get rid of the disease itself. Often, once medications are stopped, the symptoms return. Taking any medication for an extended amount of time can have significant effects on your body. It is important that you educate yourself about what medications you decide to take and understand both the short-term and long-term effects on your body. Also, medications alone for most will be insufficient to help with symptoms from endometriosis and other related conditions. A multidisciplinary approach, such as pelvic physical therapy, is necessary to enhance relief of chronic pelvic pain for the long term. 

It is also important to discuss a long term plan with your provider. As long as endometriosis lesions are present, irritation to muscles and nerves that can cause pain will continue. Addressing the underlying problem is important for long term goals. It is also important to address other pain generators, such as pelvic floor dysfunction or interstitial cystitis/bladder pain syndrome. 

Different medications can be used to help alleviate chronic pelvic pain and other related conditions. Alleviate does not necessarily mean eliminate. It is important to discuss with your provider the risks and benefits to your body, because everyone will respond differently and have other issues to consider when choosing a medication. Hormonal treatments are also meant to address pain (see “Hormonal Medications“).

Medication to treat pain might include:

  • Nonsteroidal anti-inflammatory drugs (NSAID’s): These work by decreasing the inflammatory response of your body to endometriosis. (see “Fatigue” and “Inflammation“)

“Nonsteroidal anti-inflammatory drugs are readily available without prescription for pain relief. They work by preventing or slowing down the production of prostaglandins, which helps to relieve the painful cramps associated with endometriosis. However, a Cochrane review on the use of NSAIDs for painful periods found greater risk of stomach upset (e.g. nausea, diarrhoea) or other side effects (e.g. headache, drowsiness, dizziness, dryness of the mouth).”

  • Brown, J., Crawford, T. J., Allen, C., Hopewell, S., & Prentice, A. (2017). Nonsteroidal anti‐inflammatory drugs for pain in women with endometriosis. Cochrane Database of Systematic Reviews, (1). Retrieved from https://doi.org/10.1002/14651858.CD004753.pub4

Many times, the use of nonsteroidal anti-inflammatories (NSAIDs), such naproxen, are suggested to help with pelvic pain. A meta-analysis done by Brown et al. (2017), however, couldn’t find much evidence to prove “the effectiveness of NSAIDs (specifically naproxen) for management of pain caused by endometriosis”. But the authors also point out that “nonsteroidal anti‐inflammatory drugs are readily available without prescription for pain relief. They work by preventing or slowing down the production of prostaglandins, which helps to relieve the painful cramps associated with endometriosis”. But they do caution about the side effects to the gastrointestinal system.

“NSAIDs are a type of pain medicine that can help to relieve the pain caused by endometriosis. The medicine works by stopping the release of prostaglandins, one of the main chemicals responsible for pain in general as well as painful menstrual periods. Starting these medications one to two days before your period works best to prevent prostaglandin production and therefore reduce pain. It may take some time, and several doses, for the NSAIDs to block the prostaglandin production and reduce pain. NSAIDs do not shrink or prevent the growth of endometriosis. Most NSAIDs are available without a prescription, including: Ibuprofen (sold as Advil, Motrin, and store brands) or Naproxen sodium (sold as Aleve, Anaprox, Naprosyn, and store brands). If over-the-counter NSAIDs are not effective, prescription doses and formulations may be helpful. The disadvantage of NSAIDs is that they do not always relieve endometriosis-related pain. NSAIDs probably work better when combined with another treatment, like hormonal birth control. Serious side effects from NSAIDs, although uncommon, include stomach upset, kidney problems, and worsened high blood pressure.”

“First-line medical treatment for pain due to endometriosis is often a nonsteroidal anti-inflammatory drug, either by prescription or over-the-counter. Although these antiprostaglandin agents have been shown to be effective for the treatment of primary dysmenorrhea (58), a Cochrane analysis found insufficient data to show that they significantly reduce endometriosis pain (59).”

  • Acetaminophen/Paracetamol (Tylenol): Acetaminophen, like NSAIDs, can inhibit prostaglandins that contribute to pain sensation. Some people may tolerate acetaminophen better than NSAIDs.  Because it is combined with many other over-the-counter as well as prescription medications, it is important that you examine the contents of medications you take carefully to avoid taking too much. 

“The exact mechanism of action of paracetamol is unknown, however, it is also believed to work by inhibiting central prostaglandin synthesis, and works well as a drug potentiator, increasing the effectiveness of other analgesic medications. Dose-related hepatotxicity is a major known risk of acetaminophen [27]. Few studies have identified it as an effective pain reliever alone [24]; however, when combined with NSAIDs or caffeine, paracetamol has been shown to achieve moderate levels of pain relief with menstrual pelvic pain [28,29].”

  • Muscle Relaxants: These might be used to help with cramping and muscular pain. The uterus as well as the bladder are muscular organs. Irritation to the surrounding pelvic floor muscles can also cause pain. Muscle relaxants include baclofen, tizanidine (Zanaflex), cyclobenzaprine (Flexeril) hyoscyamine, oxybutynin, or diazepam. Muscle relaxants are available to take by mouth but may be prescribed to use in a topical lotion or cream, or used intravaginally (inside of the vagina). It is important you follow the directions on the prescription from your provider.

“Muscle relaxants are also commonly used for symptom relief when pelvic floor muscle spasm is contributing to the patient’s pain. Oral muscle relaxants may help reduce overall muscle tone that is perceived to be painful but are not specific for the pelvic floor. Cyclobenzaprine, when taken daily, has an effect similar to the tricyclic antidepressants. It may be best prescribed at night given its sedative side effects. Of note, patients should be monitored for urinary retention when on cyclobenzaprine. Certain muscle relaxants, such as diazepam and baclofen can be made into a suppository or compounded cream and used intravaginally. Vaginal diazepam is generally well tolerated, with the major side effect being drowsiness. In a retrospective review by Carrico and Peters, 67% of women reported no adverse effects from the vaginal diazepam, while 33% of women reported some drowsiness.11 Topical lidocaine can also been used in the treatment of severe penetrative dyspareunia. This medication is especially useful when used prior to intercourse. Lidocaine gel can also be used internally prior to physical therapy for patients that have trouble tolerating internal myofascial release of the pelvic floor muscles.”

  • Antidepressant medications: If your provider mentions antidepressant medications, they are not suggesting it’s “all in your head”. Serotonin and norepinephrine (chemicals in the brain), which antidepressant medications affect, are implicated in pain as well as mood. (see “Pain with Endometriosis“) 

“In the brain stem, the neurotransmitters serotonin and norepinephrine modulate pain transmission through ascending and descending neural pathways. Both serotonin and norepinephrine are also key neurotransmitters involved with the pathophysiology of depression. Tricyclic antidepressants are effective treatments for pain and depression; selective serotonin reuptake inhibitors provide less benefit. Duloxetine and venlafaxine, which are serotonin and norepinephrine reuptake inhibitors, were shown in clinical trials to alleviate pain and depressive symptoms. Diabetic neuropathy and other chronic pain syndromes were also shown to benefit from duloxetine and venlafaxine. Antidepressants remain fundamental therapeutic agents for depression and anxiety disorders. Their extended use into chronic pain, depression with physical pain, physical pain with or without depression, and other potential medical conditions should be recognized.”

“Tricyclic antidepressants (TCAs) are a first-line treatment of many neuropathic chronic pain conditions, increasing the amount of available norepinephrine, thus reducing pain [32]. Unfortunately, data pertaining to CPP in women are minimal. One study randomized 56 women with CPP to amitriptyline, gabapentin to amitriptyline/gabapentin combined for 24 months. While each drug and drug combination resulted in a significantly reduced pain response, fewer side effects were noted in gabapentin alone when compared with the addition of amitriptyline [33]. Unfortunately, poor compliance and early discontinuation is common due to the anticholinergic side effects [34]. Nortriptyline and imipramine have also been studied limited in small groups of women with CPP with some improvement of pain symptoms [35,36]. The majority of the studies evaluating TCAs effect on pelvic pain is restricted to urologic pain disorders, not necessarily generalizable to women with CPP without urologic symptoms [37–40]…. Increasing the availability of serotonin may affect pain disorders. The selective serotonin reuptake inhibitors sertraline, has been studied in a single, small, placebo controlled randomized controlled trial in women with CPP, in which 23 women were randomized to sertraline or placebo. Despite 6 weeks of use, there was no notable difference in pelvic pain scores between the groups [41]. Like serotonin, norepinephrine also inhibits pain by inhibiting the descending pain pathways. Selective neurotransmitter reuptake inhibitors result in the increased availability of serotonin and norepinephrine, and have been highly successful in the treatment of many pain disorders. The significant analgesic effect may be predominately from the increase in norepinephrine centrally. While no studies have been performed in women with CPP exclusively, duloxetine has been identified as an effective pain modulator in urologic pelvic pain disorders in men and women [42,43] and is widely used in the treatment of diabetic peripheral neuropathy, fibromyalgia and chronic musculoskeletal pain [44]. Other antidepressants have shown modest improvement in chronic pain include bupropion (noradrenergic and dopaminergic pump inhibitor) and trazodone (serotonin-2 antagonist/reuptake inhibitor), though again there remains a lack of literature pertaining specifically to women with CPP.”

  • Anti-convulsant Medications: Medications such as gabapentin (Neurontin), pregabalin (Lyrica), topiramate (Topamax) are often recommended for neuropathic pain. 

“In Gabapentin group, pain was significantly reduced at 12 and 24 weeks (mean = 5.12 ± 0.67 and 3.72 ± 0.69, respectively) than in placebo group (mean = 5.9 ± 0.92 and 5.5 ± 1.13, respectively); this difference was significant. At 24 weeks, there was significantly higher proportion of patients reporting 30% or more reduction in pain scores; 19 out of 20 patients (95%) in Gabapentin group compared to 8 out of 14 patients (57.1%) in placebo group. The relative risk for pain after gabapentin treatment was 0.5 with 95% confidence interval = 0.34 to 0.75 and number needed to treat = 3 (p = 0.007). Regarding adverse effects there was significantly higher incidence of dizziness with Gabapentin (26.1%) compared to placebo (3.3%).”

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  • Opioids: Opioids are effective for pain management. They are generally used for short term acute pain (such as after surgery), break through pain, or as a last resort for chronic pain. Your provider may send you to a pain management specialist if they are considering using opioids for chronic pain management. A pain management specialist can be helpful in finding the right combination of therapies for your body. Opioids come with significant risks that should be discussed carefully with your provider. It is important to follow your provider’s direction for usage and to discuss side effects, such as nausea and constipation. Over time, your body can become tolerant to the medicine and it may not work as effectively. There is also a phenomenon called opioid-induced hyperalgesia (increased sensitivity to pain caused by opioids) that your provider will consider if medication is not effective. 

“Opioids are highly effective for acute pain and chronic malignant pain; however, their role in chronic nonmalignant pelvic pain remains controversial. In fact, there is extremely limited data on the role of opioid therapy and pelvic pain [30], opioid receptors are G-protein receptors with three known subtypes μ, δ and κ and these receptors are primarily located in the brain (cortex, thalamus and periaqueductal gray) and spinal cord. Traditionally, analgesics have directed therapy to the μ receptor or the δ receptor (though activation of the latter is responsible for the significant side effect profile that can accompany these medications despite analgesic effect) [31]. Opioid receptors are found in both the CNS and PNS and the gastrointestinal system. While excellent analgesics, the short and long-term side effect profiles remain high, and the risks of long-term opioid use should be seriously measured in reproductive aged women with CPP.”

“The adequate treatment of pain remains one of the major medical challenges. Morphine and other opioid drugs are most commonly used to counteract moderate to severe pain, but they are also increasingly accessed by patients with chronic non-malignant pain. To achieve long-term analgesia, opioid therapy still represents the standard treatment for chronic pain alleviation…. To provide sustained analgesia in chronic pain patients, regular administration of drugs is required to ensure that the next dose of an analgesic is given before the effects of the previous dose have dissipated. Unfortunately, despite advances in understanding its etiology and pathophysiology, chronic pain remains inadequately treated to date. In general, the appropriate management of chronic pain [3] aims to improve quality of life and daily function by alleviating not only pain symptoms, but also comorbid conditions…. Opioid use for treating chronic pain may be justified only in patients who have not responded to any other therapy, as long term effects of clinical and excessive use of opioid drugs can affect nearly every organ system of the body…. Overall, pain management guidelines advise the use of extended-release (ER) formulations, rather than immediate-release (IR) formulation because they provide sustained analgesia [26], [27]. For patients suffering from moderate to severe chronic pain, ER formulations represent a viable option for around-the-clock analgesia, allowing a simpler dosing schedule (‘less clock-watching’), but also a more consistent and durable pain relief.”

  • Mao, J. (2016). Practical Management of Opioid-Induced Hyperalgesia in the Primary Care Setting. In Opioid-Induced Hyperalgesia (pp. 105-112). CRC Press. 

“Beside the many known side effects of opioids such as sedation and constipation, chronic opioid exposure is associated with the development of tolerance to opioid analgesics. This process is largely due to the adaptive change of opioid analgesic system that leads to the desensitization of opioid receptors and associated cellular cascade. Another consequence of chronic opioid exposure is the development of opioid dependence. A notable feature of opioid dependence is that hyperalgesia (exacerbated painful response to noxious stimulation) occurs during a precipitated opioid withdrawal.”

“Naltrexone hydrochloride is a competitive opioid antagonist, traditionally used as a treatment for opioid addiction 6,7,8. More recently, naltrexone has been evaluated as a novel treatment for chronic pain and autoimmune disorders. When used for this indication, a significantly lower dosage of 3-4.5 mg is employed. This decreased, off-label daily dosing is typically referred to as “low-dose naltrexone” (LDN). Using lower doses exploits naltrexone’s ability to act (directly on microglia cells of the) on the central nervous system, in addition to its more widely known action at opioid receptors6 . Prior studies suggest that LDN may be beneficial in patients with fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. Evidence shows that LDN can function as an anti-inflammatory agent, acting on non-opioid receptors of central nervous system microglia cells (Liu). The non-opioid pathway decreases activation of microglia, blocking TNF alpha synthesis, among multiple other inflammatory factors. Reduced plasma levels of pro-inflammatory cytokines have been seen with use of LDN7,8. Given that endometriosis is characterized by increased peritoneal inflammation, patients may benefit from the nontraditional anti-inflammatory properties of LDN. Additionally, LDN has been shown to intermittently block all 3 subtypes (µ,κ,δ) of opioid receptors. The transient blockade results in an upregulation of endogenous opioids and opioid receptors. This rebound elevation of endogenous opioid levels may improve endogenous analgesia and further enhance QOL in patients with chronic pain 6.”

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Saeid Gholami

Dr. Saeid Gholami is a medical doctor and the founder of iCareBetter. As a physician, he saw many patients with endometriosis who were suffering. And his patients had to deal with many unanswered questions, misleading information, and the lack of access to qualified experts. For that reason and to combat this issue, he built iCareBetter to optimize how patients and doctors connect.

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