There is well-established epidemiologic evidence demonstrating variance in the pain disorders affecting women compared with men, although limited conclusive evidence exists regarding the pathophysiologic mechanisms to account for this difference. Six of the most common pain disorders affecting women include migraine headache, fibromyalgia, endometriosis, interstitial cystitis, temporomandibular disorders, and osteoarthritis. The sex-specific prevalence, risk factors, triggers, presentations, and treatments of these disorders are critical for physicians to appreciate and understand to provide the highest standard of care when treating these common pain conditions.
Key points
- •
Men and women experience pain stimuli and pain states differently.
- •
Some of the most common women pain disorders are migraine headache, fibromyalgia, endometriosis, interstitial cystitis, temporomandibular joint disorder, and osteoarthritis.
- •
Treatment of any pain syndrome requires careful consideration of multiple factors, including gender, as well as the development of a multidisciplinary treatment plan.
Introduction/Background/History
Epidemiologic data suggest that women are at higher risk for several clinical pain conditions in relation to their male counterparts. Studies have suggested that sex differences exist in pain perception and pain tolerance to different painful stimuli, with women in particular exhibiting lower tolerance to certain stimuli. , Several hypotheses have been advanced to explain these gender disparities, including sex hormone differences as well as genetic or reproductive factors, but none of these have amounted to strong evidence on their own. Historically, it has been accepted that women-specific pain issues have often gone undertreated, have not been well understood, or have been outright ignored. To foster health-equity regarding sex differences, this brief review sheds light on a small group of “most common” clinical pain disorders among a larger subset. This article reviews the diagnoses of migraine, fibromyalgia, endometriosis, temporomandibular disorder (TMD), interstitial cystitis (IC), and osteoarthritis.
Section 1: Migraines
Definition and pathophysiology
Migraines are a genetically influenced, complex subcategory of headaches with distinctive features. Migraines are broadly categorized as those with and without aura. An aura usually precedes the migraine attack and is characterized by a reversible neurologic disturbance manifesting in changes in vision, sensation, speech, motor, and brainstem functions. Acute migraine attacks generally last between 4 and 72 hours. The diagnosis of migraine is based on the International Classification of Headache Disorders criteria. Chronic migraine is defined as headaches occurring on 15 or more days per month for greater than 3 months, with migraine features on at least 8 days per month. The prevailing and most widely accepted pathophysiologic mechanism of migraine is the theory of cortical spreading depression, where neuronal depolarizations are followed by activity suppression, resulting in changes to cortical blood flow. Other proposed mechanisms include the neurovascular and vascular theories.
Prevalence and sex differences
Because of the difficulties in making accurate diagnoses, the prevalence of migraine headaches is difficult to precisely measure. The estimated prevalence of migraines worldwide is rising and currently stands at 14% to 15%, with a higher prevalence in women at nearly 19%. While many theories have been proposed regarding the sex differences in migraine prevalence, many lack robust supportive evidence. Two such theories include higher pain thresholds in women compared with men, as well as sex-variable pharmacokinetic and pharmacodynamic responses to analgesics. The most likely proposed mechanism, based on available evidence, is that of hormone differences: fluctuations in estrogen, progesterone, and androgens have been shown to have variable effects on the risk of migraine attacks. For example, premenstrual changes in hormone concentrations are associated with a higher risk of migraine attacks, whereas rates tend to improve during pregnancy, a time when hormone levels remain relatively stable.
Symptoms
Migraines present as unilateral throbbing or pulsatile pain, moderate to severe intensity, and frequently include a combination of nausea, vomiting, sensitivity to light and sound, and a preceding aura. Symptoms tend to worsen with physical activity. Migraine attacks in women tend to be of longer duration, increased intensity, and with more frequent photophobia, phonophobia, nausea, and vomiting compared with men. However, men tend to experience aura more frequently than women.
Causes
Broadly speaking, migraine triggers can fall into 5 categories: emotional stress, hormone related, sleep disturbance, food and alcohol, and weather changes. The most common triggers, in order, include stress, hormonal changes (premenstruation), fasting, weather fluctuations, and sleep disturbances.
Treatment and rehabilitation
The goal of treatment and rehabilitation is to reduce/decrease the frequency of migraines, pain, and improve quality of life. Treatment strategies span from patient education on lifestyle changes and trigger avoidance to abortive and prophylactic interventions. Identifying and managing known triggers is a crucial first step in the management of migraines. While sleep disturbance is not the most common trigger for migraines, it serves as a fundamental aspect of one’s health with many deleterious effects when compromised, and therefore must be prioritized. The mainstay of acute, abortive treatment includes non-steroidal anti-inflammatory drugs (NSAIDs), triptans, and newer medications such as calcitonin gene-related protein (cGRP) receptor antagonists. The effectiveness of abortive treatments is highly correlative with earlier administration after initial symptom onset. Preventative medications should be tailored to the individual patient and can include beta-blockers, antidepressants, and antiepileptic medications. Additionally, the use of botulinum toxin type via the Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) protocol has shown significant efficacy in chronic migraine prevention. As previously discussed, there is a lack of evidence proving a differing or variable effectiveness of migraine treatments in women compared with men.
Section 2: Fibromyalgia
Definition and pathophysiology
Fibromyalgia is a disorder characterized by widespread musculoskeletal pain. Patients with fibromyalgia display an increased sensitivity to a range of sensory stimuli which in a healthy individual would not usually evoke a pain response. Evidence suggests that these changes in the perception of nonpainful stimuli as painful ones are mediated through neurochemical changes in the dorsal horn of the spinal cord and in the central nervous system (CNS). , The International Association for the Study of Pain (IASP) refers to this type of pain as nociplastic pain, explained as pain that “arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.”
Prevalence and sex differences
The overall prevalence of fibromyalgia is between 6% and 7% in the United States, with European and South American studies showing a broader range of 3.3% to 8.3%. Fibromyalgia is more prevalent in women than men; in the United States, one study found the prevalence to be 7.7% in women and 4.9% in men, while a larger systematic review found that fibromyalgia is 8 to 9 times more common in women than in men. A large study of German patients concluded that women reported more symptoms, more generalized pain, and the same study also suggested a linear relationship between being female and the presence and severity of fibromyalgia.
Symptoms
Patients with fibromyalgia may often complain of accompanying symptoms including sleep disturbances, depression, cognitive disorders, gastrointestinal symptoms, poorly localized tingling sensations in the trunk or limbs, or morning stiffness. , It is not uncommon for these patients to also present with chronic fatigue syndrome, tension-type or migraine headaches, irritable bowel syndrome (IBS), or mood disorders. Prolonged pain and sleep disturbances inherent to this disorder can be associated with “fibro fog” manifesting as memory impairment and impaired focus or attention to tasks. These issues can contribute to fatigue, anxiety, catastrophizing, as well as reported work and/or family life challenges. These patients may present with overlapping pain conditions; most commonly chronic low back pain, interstial cystitis (IC), or temporomandibular joint (TMJ) disorder. The diagnostic criteria for fibromyalgia as put forth by the American College of Rheumatology require exclusion of any other diagnoses that would explain the patient’s pain, symptomatology of a consistent level lasting at least 3 months, and the use of both widespread pain index and symptom severity score of specific minimums.
Causes
Fibromyalgia is considered a stress-related disorder and has been linked to alterations in cortisol suppression, with patients studied showing overall higher levels of plasma cortisol. This suggests that these patients might be more susceptible to traumatic experiences which would cause cortisol elevations and potentially contribute to this disease state. Fibromyalgia can be grouped into a family of affective spectrum disorders, including rheumatoid arthritis and major depressive disorder, which all appear to share a common genetic heritage, with first degree family members showing enhanced sensitivity to pain, but without clear elucidation of the genes responsible.
Treatments
The mainstay of recommended treatments for fibromyalgia is centered around physical therapy and lifestyle changes with emphasis on aerobic exercise and improving sleep. Patients often struggle to persist with exercise and/or physical therapy interventions secondary to fatigue and pain, requiring a measured approach and encouragement. Several medications have been suggested as possible adjunctive therapies to these mainstays. These include but are not limited to serotonin-norepinephrine reuptake inhibitors (duloxetine, milnacipran), anticonvulsants (gabapentin, pregabalin), nonsteroidal anti-inflammatory drugs, tricyclic antidepressants (amitriptyline, desipramine), and muscle relaxants (cyclobenzaprine, methocarbamol). In general, these medications show “weak evidence” at best in treating fibromyalgia. Optimization of nutrition to address any deficiencies may be a promising avenue. Cognitive behavioral therapy (CBT), meditation, and/or mindfulness approaches to treating fibromyalgia are commonly employed despite also showing weak evidence and may be beneficial in addressing patient’s common comorbid mood disorders.
Rehabilitation
The gentle initiation of a physical therapy regimen is useful in helping patients establish their own successful home exercise routine. This is also done to foster resilience and to strengthen positive coping mechanisms. Rehabilitation of this nature has been shown to expand patients’ coping repertoire by offering new symptom management options as well as fostering confidence in using said options on a more consistent basis. Patients should also be encouraged to learn stress reduction techniques and may be formally referred for such training with psychology or other professional counselors.
Section 3: Endometriosis
Definition and pathophysiology
Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows outside the uterus. There are immunologic, genetic, and hormonal factors that may lead or increase risk of developing endometriosis. In many patients, this disorder is associated with chronic pelvic and/or abdominal pain often associated with infertility. Location of the ectopic tissue may vary and includes superficial peritoneal, ovarian, deep, extra-abdominal, and iatrogenic (eg, after cesarean section) endometriosis.
Prevalence in women
Endometriosis affects approximately 190 million women and patients who are female gender at birth worldwide. Unfortunately, the time to diagnosis in almost 60% of affected patients is delayed. Females will see 3 or more clinicians over an average of 7 years for evaluation and treatment before an appropriate diagnosis of endometriosis is made. Like other chronic conditions, women will lose on average 11 hours of work per week due to their endometriosis-related symptoms. Patients with endometriosis have an increased risk by 2-fold for infertility compared with patients without endometriosis.
Symptoms
Endometriosis includes a range of painful symptoms such as, chronic pelvic pain (cyclical and noncyclical), menstrual irregularities, dyspareunia, dysuria, painful defecation, and infertility. Severity of pain symptoms are variable and do not necessarily correlate with the “severity” of the anatomic disease.
Causes
The most probable cause of endometriosis is reflux of endometrial tissue cells and protein rich fluid through the fallopian tubes into the pelvis during menstruation. However, this does not fully explain etiology as many women experience retrograde menstruation and do not develop this disease process. The eutopic endometrial tissue in a patient with endometriosis has a different immune profile compared with individual without it. Yet, it remains unclear if this is the cause or effect of endometriosis. Shed endometrial tissue has pro-inflammatory cytokines, proteases, and immune cells (eg, tumor necrosis factor [TNF]-alpha, interleukin [IL]-1B, and nerve growth factor) that may trigger endometrial lesions. Although chronic pelvic pain is a primary presenting symptom, patients with endometriosis have higher associated risk for comorbid pain conditions such a fibromyalgia, migraines, rheumatological disorders, and osteoarthritis. Almost half of patients with IC have endometriosis. Similarly, patients with IBS are at risk of co-occurring endometriosis. These conditions may share a common cause owing to environmental and genetic factors.
Treatments
Ultrasound and MRI can be used to diagnose endometriosis preoperatively, but diagnostic laparoscopy with potential excision of lesions is often required. Hormonal contraceptives, gonadotropin-releasing hormone agonists and antagonists, and progestin therapy are commonly used for the treatment of this disease process. Untreated pelvic pain caused by endometriosis can lead to central sensitization, a phenomenon which results in a chronic pain syndrome due to a “wind-up” of their CNS. This leads to refractory symptoms despite conservative and surgical treatment stressing the importance of early diagnosis and treatment. Timely referral to a pelvic pain specialist for a comprehensive, multidisciplinary pain management program, including consideration of sympathetic blockade (eg, hypogastric and/or ganglion impar blocks), peripheral nerve blocks, and trigger point injections can help patients improve symptoms and regain function. ,
Rehabilitation
Regular exercise and stress management techniques can help manage endometriosis. Pelvic floor physical therapy is a mainstay of treatment of chronic pelvic pain syndrome. A recent study demonstrated the benefit of a comprehensive treatment protocol utilizing a full course of pelvic floor physical therapy (PT) combined with ultrasound-guided nerve blocks and trigger points injections.
Section 4: Interstitial Cystitis
Definition and pathophysiology
IC is a chronic condition (>6 weeks) causing bladder pressure and bladder pain that is refractory to treatment. It is characterized by chronic inflammation of the urinary tract, which is not due to infection or other identifiable causes. The mechanism is not well understood and often is misdiagnosed or diagnosed late, especially in men. Pathogenesis is most likely multifactorial. Cystoscopy in patients with IC shows submucosal inflammation with glomerulations (Hunner’s lesions).
Prevalence in women
The most common prevalence is in women between 50 and 59 years of age and men between 56 and 74 years of age. It is significantly more common in females than males, with 1 study noting a 5:1 ratio predominance in females.
Symptoms
IC symptoms include chronic pelvic pain, a persistent urge to urinate, and frequent urination. Patients may describe pain in the bladder or suprapubic region, with severe urinary urgency. Dyspareunia in women and ejaculatory pain in men may occur. Symptoms are often refractory to standard treatment for overactive bladder therapy. Patients may develop chronic pelvic pain that significantly impacts wellbeing and quality of life.
Causes
Left untreated, chronic inflammation of the urothelium can lead to chronic pelvic pain syndrome. Large groups of mast cells are frequently present that stimulate afferent sensory fibers causing afferent hyperactivity and nociceptive upregulation. Loss of tight junction and adhesive junction proteins cause a “leaky urothelium” associated with submucosal microvascular abnormalities and lack of normal bladder epithelial cell growth. IC has been closely associated with autoimmune diseases such as Hashimoto’s thyroiditis, rheumatoid arthritis, ankylosing spondylitis, IBS, fibromyalgia, chronic fatigue, and especially Sjogren syndrome.
Treatments
Initial treatment for IC should be based on dietary and lifestyle modifications, specifically in reducing common irritants. Common bladder irritants include alcohol, benzyl alcohol, caffeine, carbonated beverages, coffee, chili, spices, sweeteners, tomato-based products, and vinegar. Pain management with a multimodal approach is recommended. This may include oral analgesics (nonopioid preferred) and bladder instillations (cocktail of medications ranging from lidocaine, corticosteroids, dimethyl sulfoxide, heparin, hyaluronic acid, and misoprostol). Botox injections for overactive detrusor muscle have also been employed and supported in the literature. In refractory cases, neuromodulation with sacral or dorsal root ganglion stimulator can be considered. There is some evidence for tibial nerve stimulation for the treatment of IC. , Surgical intervention is a last resort but may provide relief for up to 75% of patients.
Rehabilitation
Myofascial release, physical therapy with relaxation exercises, and pelvic floor trigger point manual therapy provided by a skilled practitioner have shown significant symptom relief in 70% of patients. Interestingly enough, standard pelvic floor PT in isolation is not recommended as it may worsen symptoms. Stress reduction activities like yoga, meditation, and massage can help manage IC.
Section 5: Temporomandibular Disorders
Definition and pathophysiology
TMDs are a group of orofacial pain conditions involving either the masticatory muscles and/or the TMJ. Myofascial TMD involves the muscles of mastication becoming overused, fatigued, and painful, developing potential trigger points. Causation is multifactorial but can include bruxism, increased stress levels or anxiety, mechanical or postural abnormalities, autoimmune disease, or fibromyalgia. The most involved muscles are the 4 primary muscles of mastication: temporalis, medial pterygoid, lateral pterygoid, and masseter. Articular TMD is caused by derangement of the TMJ articulation formed between the glenoid fossa of temporal bone and the mandibular condyle. Within this joint, an articular disc splits the joint into 2 synovial cavities (superior and inferior) with 2 distinctive movements characterized: translatory side to side movement in the superior portion and hinge movement of the jaw in the inferior portion. A slew of mechanical, traumatic, inflammatory issues can cause joint pain, with displacement of the articular disc being the most common etiology of TMJ-based pain.
Prevalence in women
The global prevalence of TMD has a large range. A recent systematic review of TMD epidemiology suggests that the prevalence of “severe” TMD overall is about 10% most common to occur between the ages of 25 to 45. Almost every study included in the same review suggested that prevalence is higher in women as compared with men, with one large study suggesting that TMD prevalence for women was nearly 4 times higher than men. This considerable gender difference combined with the common age range during “reproductive years” has led to hypotheses about the roles that the reproductive hormones may have on this condition.
Symptoms
TMD is a clinical diagnosis, and therefore requires a careful history and examination to correctly identify it as the most likely diagnosis. Patients often complain of pain at the TMJ or mandible as the primary symptom, with pain sometimes radiating to the head or neck. Pain is usually exacerbated by mastication, yawning, or prolonged talking, and patients may report clicking, popping, crepitus, and even locking or difficulty opening/closing the mouth. Orofacial pain not associated with jaw movement is suggestive of a diagnosis besides TMD. Tension-type headaches can be associated with TMD, and some patients may also report otalgia, tinnitus, vertigo, and even hearing impairment as well.
Causes
The cause of TMD is often multifactorial. Etiologies of TMD can be grossly divided into myofascially derived pain versus intraarticular disorders of the TMJ. Certain behaviors, such as bruxism (grinding, clenching, or gnashing of the teeth) as well as psychological factors like stress and anxiety, can be linked to muscular pain. Certain diagnoses such as depression, anxiety, autoimmune disorders, and fibromyalgia share associations with TMD. Derangements of the TMJ itself may be linked to osteoarthritis, hypermobility, or trauma. The most likely inflammatory causes of TMJ pain are rheumatoid arthritis and ankylosing spondylitis.
Treatments
Forty percent of patients with TMD will have spontaneous resolution of symptoms, and one long-term study determined that between 50% and 90% of patients had pain relief after conservative care. Patient history and physical examination suggestive of trauma, dislocation, infection, or abscess warrant imaging (eg, X ray or computed tomography [CT]) and referral to a dentist or surgeon. Otherwise, treatment should be focused on resolving pain and restoring function. First-line agents are often NSAIDs. Muscle relaxants, antidepressants, or gabapentinoids have some support for pain reduction and are offered as adjuncts. CBT has level B evidence for improving short-term and long-term pain in TMD. Diagnostic trigger point injections can be done in the suspected musculature involved. Intraarticular injection is indicated for pain control and improved function in severe TMJ but should be done with caution to prevent further degradation of articular cartilage. Surgical referral should be reserved for patients with clear acute indications above or those who have failed conservative treatment. Referral to a dentist should be considered in cases of poor dental health, caries, and suspected grinding that might be amenable to occlusal splinting.
Rehabilitation
Physical therapy is a commonly used treatment for TMD with various treatments focused on decreasing neck and jaw pain, improving range of motion, and promoting home exercise habits. Exercises of the muscles of mastication as well as musculature of the neck can be combined with manual therapy and other passive modalities. However, a large systematic review of therapeutic exercise and manual therapy for TMD did not show high-level evidence for these interventions citing tremendous heterogeneity in treatment types and regimens.
Section 6: Osteoarthritis
Definition
Osteoarthritis is a degenerative joint disease characterized by the progressive breakdown of the joint. The disease manifests first as a molecular derangement of normal joint metabolism and is followed closely by anatomic and physiologic derangements characterized by cartilage degradation, bone remodeling, osteophyte formation, joint inflammation, and maladaptive joint functioning.
Epidemiology
Osteoarthritis is the most common form of arthritis. The global prevalence of osteoarthritis is roughly 528 million, 60% of which are women. Prevalence of osteoarthritis increases with age, affecting roughly 10% of men and 18% of women aged 60 and older. Rates also vary by affected joint, with women being affected more with hand and knee osteoarthritis while men are affected more by hip osteoarthritis. ,
Symptoms
Osteoarthritis is characterized by pain and stiffness in the affected joints. Stiffness is worse in the morning or after prolonged inactivity and tends to improve within 30 minutes of initial activity, contrasting that of inflammatory arthritis where stiffness tends to remain for longer than 1 hour. On examination, osteoarthritis is usually associated with either absent or small effusions (such as in the knees), reduced range of motion with crepitus, and bony enlargement (such as Heberden’s nodes). The classic radiographic triad of osteoarthritis includes joint space narrowing, osteophyte formation, and subchondral sclerosis.
Pathophysiology
The pathophysiology of osteoarthritis involves a complex interplay of mechanical, biochemical, and genetic factors affecting cartilage, bone, synovium, ligaments, periarticular fat, and muscle. A classic example of how abnormalities in biomechanical alignment contribute to the development of osteoarthritis can be observed in the elevated rates of knee osteoarthritis in women. In general, the relatively wider hips seen in women create a greater Q-angle and resultant knee valgus alignment which can asymmetrically load the lateral knee compartment and contribute to knee osteoarthritis. While there have been numerous papers devoted to addressing the question of whether hormones (including estrogen) play a role in the development or prevention of osteoarthritis, there is currently no definitive, clinically meaningful conclusion regarding this topic.
Rehabilitation and treatment
The mainstay of osteoarthritis prevention includes optimizing fat-free body mass by promoting muscle development, increasing flexibility, improving metabolic health, and avoiding joint trauma and biomechanical inequalities. In treating symptomatic osteoarthritis, physician-directed exercise programs and formal physical and occupational therapy are the best first approaches to treatment and are aimed at addressing the previously stated elements of disease prevention. Durable medical equipment such as heel wedges, orthotics, braces, and splints can be used to correct causative biomechanical asymmetries. Initial pharmacologic treatments should include the use of short courses of acetaminophen, oral and topical NSAIDs, as well as ice, heat, lidocaine patches, and menthol-containing lotions. Adjunctive medications such as serotonin-norepinephrine reuptake inhibitors (eg, duloxetine) and anticonvulsants (eg, gabapentin) can be considered for more chronic cases of symptomatic osteoarthritis. Should these initial steps fail, the use of corticosteroids, hyaluronic acid, platelet-rich plasma injections, and genicular nerve blocks/ablations can be considered prior to consideration of more invasive treatments such as joint replacements.
Discussion
The 6 pain disorders chosen for this review demonstrate the stark differences in prevalence among the sexes and serve to highlight the important role that rehabilitation physicians play when diagnosing and treating women patients. The prevalence of several painful clinical diagnoses is higher for women as compared with men, and among patients with chronic pain conditions who are admitted to rehabilitation units, more are women than men. Exercise has been implicated as an intervention with high level of evidence for fibromyalgia, helping to improve symptoms, function, and decrease fatigue. Physical therapy and exercise are also mainstays of treatment for TMD, chronic pelvic pain (in setting of endometriosis and/or IC), and osteoarthritis. , , , , , , However, it is not well understood which therapeutic exercises or modalities are best suited to treat each sex, and further research is required. Patients with chronic pain conditions benefit most from evaluation by a multidisciplinary team comprising physicians, psychologists, nurses, physical and occupational therapists. Each individual patient may benefit from disease-specific referral to a specialist, for early evaluation and targeted medical care. Much remains to be elucidated about sex differences in pain syndromes and how these differences might best be considered when planning evidence-based care for optimal patient outcomes.
Summary
There is ample evidence to suggest that certain pain conditions affect women to a greater extent and in varying ways compared with men. The underlying pathophysiologic mechanisms, while hypothesized, remain largely inconclusive. Six of the more common pain conditions affecting women include migraine headache, fibromyalgia, endometriosis, IC, TMJ disorder, and osteoarthritis. Future research should address the underlying sex-specific mechanisms of these disorders, with particular attention given to pharmacologic, interventional, and rehabilitative treatment options that will allow physicians to provide the highest standard of care for women.
Clinics care points
- •
Aerobic exercise has the strongest evidence for the treatment of fibromyalgia.
- •
Exercise and physical therapy are mainstay modalities for treatment of temporomandibular disorder and osteoarthritis.
- •
Interstitial cystitis and endometriosis can contribute to chronic pelvic pain syndrome.
- •
Botox for migraines is an established treatment, but overall migraine management requires a multidisciplinary approach.
- •
Men and women experience pain stimuli and pain states differently, and therefore sex and gender should be considered in tailoring treatment for each patient.
Related posts:
Rehabilitation Considerations in Women with Traumatic Brain Injury
Cardiac Rehabilitation for Women with Heart Disease
Rehabilitation Considerations for Women with Spinal Cord Injury
Pelvic Pain and Pelvic Floor Disorders in Women
Reproductive and Sexual Health Considerations for Adolescent Females with Disabilities
Osteoporosis Issues Regarding Rehabilitation in Women
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
