Vasomotor symptoms are not a minor inconvenience. According to the guideline, they are the most common symptoms associated with menopause, affecting up to 80 percent of women. They typically begin during perimenopause, the transitional phase before menstruation stops permanently, when declining and fluctuating levels of reproductive hormones destabilize the body’s temperature regulation. The result is the sudden, often intense sensation of heat known as a hot flash, frequently accompanied by sweating, flushing, and a racing heart, as well as night sweats that can drench sleepwear and interrupt rest. The guideline notes that these episodes can persist well into the postmenopausal years, and that their frequency and severity can disrupt daily activities and erode quality of life.

The physiological story behind vasomotor symptoms is rooted in estrogen. As ovarian function wanes, estrogen levels fall and fluctuate unpredictably, and this hormonal instability is thought to narrow the thermoneutral zone in the brain’s temperature-regulating machinery, making small shifts in core body temperature trigger full heat-dissipation responses. The consequences ripple outward: the guideline highlights that the same hormonal changes can contribute to sleep disturbance, weight fluctuations, anxiety, depression, and genitourinary symptoms, creating a cluster of complaints that often arrive together and compound one another. A woman whose nights are repeatedly broken by hot flashes may also face worsening mood and concentration problems the next day, which is why effective treatment of vasomotor symptoms can have benefits well beyond the episodes themselves.

In developing the recommendation, ACP drew on a related systematic review and meta-analysis, also published in Annals of Internal Medicine, that evaluated pharmacologic treatments for menopausal vasomotor symptoms. The college concluded that estrogen in combination with progestogen, and estrogen monotherapy for women without a uterus, had the most favorable profile of benefits compared with harms among the available options. The addition of progestogen for women with an intact uterus is a long-standing safety principle in hormone therapy, because unopposed estrogen can stimulate the uterine lining and increase the risk of endometrial problems; pairing it with progestogen protects the uterus while preserving estrogen’s effectiveness against hot flashes.

The guideline does not treat hormone therapy as the only option, and it lays out a clear sequence for women who cannot or do not wish to take estrogen. For patients who have contraindications to estrogen therapy or who do not tolerate it, ACP suggests serotonin-norepinephrine reuptake inhibitors, or SNRIs, as second-line treatment, specifically naming desvenlafaxine and venlafaxine. These medications, better known as antidepressants, have demonstrated the ability to reduce the frequency and severity of hot flashes through their effects on neurotransmitter signaling pathways that participate in temperature regulation.

If SNRIs are unsuitable or ineffective, the guideline moves to a third tier of options: a selective serotonin reuptake inhibitor, or SSRI, such as escitalopram or paroxetine; gabapentin, a medication originally developed for seizures and nerve pain that also dampens hot flashes; or a neurokinin receptor antagonist, abbreviated NKra, with elinzanetant and fezolinetant named as the agents in this class. The neurokinin receptor antagonists represent a distinctly newer approach, targeting the neuropeptide signaling pathway in the brain’s thermoregulatory circuitry that becomes overactive as estrogen declines. Their inclusion among third-line options reflects the recent arrival of these drugs as nonhormonal treatments designed specifically for vasomotor symptoms.

Beyond the specific drug rankings, ACP places strong emphasis on how treatment decisions should be made. The college advises clinicians to use an informed decision-making approach, discussing with each patient the benefits and harms of the available options, any contraindications, coexisting medical conditions, and the patient’s own values and preferences. Notably, the guideline also directs physicians to consider the financial burden of treatment and patients’ access to and availability of the various therapies, an acknowledgment that the best medication on paper is of little use if a patient cannot afford it or obtain it. This framing treats the choice of therapy as a collaborative process rather than a one-size-fits-all prescription.

ACP also draws attention to a quieter problem: many women never raise the topic at all. The college encourages physicians to ask their patients directly about their experience with menopausal vasomotor symptoms, because many women may not initiate these discussions on their own. Whether due to embarrassment, the cultural normalization of suffering through menopause, or the belief that nothing effective is available, women’s silence about hot flashes and night sweats can leave treatable symptoms unaddressed for years. By prompting clinicians to open the conversation, the guideline aims to close the gap between the large share of women affected and the smaller share who receive care.

The timing of the guideline reflects a broader shift in how the medical community views menopausal hormone therapy. After years in which safety concerns led many clinicians and patients to avoid estrogen-based treatment, accumulating evidence has allowed organizations to identify the women for whom hormone therapy offers the clearest net benefit, particularly those seeking relief from bothersome vasomotor symptoms. By naming estrogen therapy as first-line, ACP is signaling to internists and primary care physicians, who manage the majority of menopausal care, that withholding hormone therapy from appropriate candidates is no longer the default stance. The guideline’s tiered structure gives clinicians a practical pathway for the many patients who have contraindications to estrogen, such as those with a history of certain hormone-sensitive cancers or cardiovascular events, without leaving them without options.

For the roughly eight in ten women who will experience hot flashes or night sweats as they pass through the menopausal transition, the practical message of the new guideline is that effective treatments exist and that the choice among them can be tailored to individual health circumstances and preferences. Women with a uterus considering first-line therapy will receive estrogen plus progestogen; women without a uterus can receive estrogen alone; those who cannot take estrogen have a defined ladder of nonhormonal alternatives ranging from SNRIs to SSRIs, gabapentin, and neurokinin receptor antagonists. Equally important, the guideline reframes the clinical encounter itself, urging physicians to ask about symptoms that patients may not volunteer and to weigh cost and access alongside efficacy and safety. The full guideline and its accompanying evidence review are published in Annals of Internal Medicine, and together they provide the most current roadmap from the American College of Physicians for managing one of the most common and disruptive experiences in women’s health.

Subject of Research: Clinical guideline recommendations for pharmacologic treatment of menopausal vasomotor symptoms

Article Title: ACP recommends hormonal therapy as a first-line treatment for menopausal vasomotor symptoms

Article References: ACP recommends hormonal therapy as a first-line treatment for menopausal vasomotor symptoms. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: menopause, vasomotor symptoms, hot flashes, hormone therapy, estrogen, progestogen, SNRI, SSRI, gabapentin, neurokinin receptor antagonist, clinical guideline, Annals of Internal Medicine

The scale of the problem is enormous. The review’s authors report that roughly 34 percent of patients worldwide experience CIPN six months or longer after finishing chemotherapy, with prevalence peaking at around 68 percent during the first month after treatment. Symptoms arise because neurotoxic drugs damage the myelin sheaths, axons, and neuronal cell bodies of the dorsal root ganglia, triggering neuroinflammation, elevated pro-inflammatory cytokines, apoptosis, and altered neuronal excitability. Clinicians distinguish positive symptoms, such as allodynia, hyperalgesia, dysesthesia, and paresthesia, from negative symptoms like numbness and motor dysfunction. In severe cases, the condition forces oncologists to reduce chemotherapy doses or abandon potentially curative regimens altogether, making effective symptomatic treatment a genuine clinical priority.

International guidelines from the American Society of Clinical Oncology and the European Society for Medical Oncology currently identify duloxetine, a serotonin-norepinephrine reuptake inhibitor, as the only pharmacological option supported by strong evidence for painful CIPN, though its use remains off-label. The foundational evidence came from a randomized placebo-controlled trial by Smith and colleagues, later confirmed by Hirayama and coworkers in a large open-label Japanese study. Yet clinical practice has moved on, with growing interest in combination and multimodal approaches, and the comparative evidence base had never been systematically consolidated. The new review set out to fill exactly that gap, synthesizing studies published between 2019 and 2025 under contemporary diagnostic and reporting standards.

Methodologically, the review was rigorous and transparent. Two investigators independently searched PubMed, Web of Science, and Scopus following PRISMA guidelines and the PICO framework, with the protocol registered on PROSPERO. From 892 initial records, 374 duplicates were removed, and successive rounds of screening excluded pre-2019 publications, preclinical studies, reviews, editorials, and inaccessible or irrelevant articles. Eleven clinical studies survived the selection process, spanning randomized double-blind placebo-controlled trials, a non-inferiority trial, prospective pilot work, retrospective observational cohorts, and individual case reports. Risk of bias was assessed with the Cochrane RoB 2 tool for randomized trials and the Newcastle-Ottawa Scale for observational studies, and most randomized trials showed low risk across the key domains of randomization, blinding, and outcome measurement.

The patient populations were heterogeneous, reflecting the diversity of oncology practice. Enrolled individuals had breast, gastrointestinal, lung, hematological, head and neck, genitourinary, and other malignancies, with sample sizes ranging from single-patient case reports to more than 230 participants. The antidepressants evaluated included duloxetine at daily doses of 20 to 60 milligrams, oral amitriptyline at 10 to 20 milligrams, topical 10 percent amitriptyline gel, and venlafaxine, alongside combination regimens pairing duloxetine with mirogabalin at 5 to 25 milligrams daily or tapentadol at 50 to 500 milligrams daily. Pain outcomes were tracked with the Numerical Rating Scale, the Visual Analogue Scale, and the Brief Pain Inventory, while neuropathy severity was graded using CTCAE criteria, the Total Neuropathy Score, and the DN4 questionnaire.

The results for duloxetine monotherapy were strikingly consistent. In one double-blind placebo-controlled trial in non-metastatic breast cancer patients receiving paclitaxel, duloxetine cut average pain scores on the Numerical Rating Scale from 4.19 to 2.63 over eight weeks, while CTCAE neuropathy grades fell from 1.48 to 0.79, a statistically significant difference against placebo. A second placebo-controlled trial in gastrointestinal cancer patients treated with oxaliplatin similarly found that duloxetine prevented worsening of peripheral sensory neuropathy, with grade scores improving from 0.86 to 0.62. In a broader randomized trial across multiple tumor types, 44.1 percent of duloxetine-treated patients achieved a clinically significant pain reduction of at least 30 percent, compared with only 18.2 percent on placebo, and 32.4 percent achieved reductions of 50 percent or more versus 3.0 percent of placebo patients. A retrospective observational study was the outlier, reporting only a modest, statistically insignificant Visual Analogue Scale change, likely reflecting uncontrolled dosing and confounding.

Combination therapies generated the most eye-catching numbers, though the authors are careful about interpretation. In a randomized study of 72 breast cancer patients, duloxetine paired with electrostimulation reduced average pain scores from about 6.1 to 3.6 in two weeks. A single case report described mirogabalin plus duloxetine lowering pain scores from 8 to 1 and CTCAE grade from 3 to 1. In a randomized non-inferiority trial of 114 patients, tapentadol combined with duloxetine reduced the Numerical Rating Scale from 7.51 to 2.87, statistically equivalent to tapentadol alone. A prospective randomized comparison of 89 patients found duloxetine outperforming pregabalin on both pain and DN4 neuropathy scores, with duloxetine dropping scores from roughly 7 to 4 over four weeks. Meanwhile, a retrospective cohort in lung cancer showed duloxetine plus low-dose mirogabalin reducing median pain scores from 5.5 to 4.0. Importantly, adverse events remained mild across all regimens, limited mainly to nausea, constipation, dizziness, and transient somnolence, and combination treatments did not increase side-effect burdens relative to monotherapy.

One of the more intriguing findings concerned topical amitriptyline. In a prospective pilot study of 44 patients treated with bortezomib or oxaliplatin, a 10 percent topical amitriptyline emulsion applied twice daily for six months reduced Visual Analogue Scale scores from 7 to 2, with the difference reaching high statistical significance. Topical delivery may offer localized analgesia with far better tolerability than systemic tricyclic therapy, which is otherwise limited by dry mouth, weight gain, and drowsiness. The evidence base remains small, but the result hints at a practical option for patients who cannot tolerate oral agents, and it underscores how routes of administration may reshape the pharmacology of otherwise old drugs.

Why should antidepressants relieve nerve pain at all? The review explains the mechanistic logic. SNRIs like duloxetine and tricyclics like amitriptyline enhance both serotonergic and noradrenergic transmission, strengthening descending inhibitory pathways, particularly noradrenergic projections from the locus coeruleus to the spinal dorsal horn that suppress pain signals before they reach consciousness. Selective serotonin reuptake inhibitors, by contrast, fail to engage these noradrenergic circuits, which may explain their inconsistent efficacy in neuropathic pain. Preclinical work supports these mechanisms, with duloxetine, amitriptyline, and pregabalin all reducing pain behaviors in animal models, although translational gaps persist, especially for pregabalin and venlafaxine, which perform better in the laboratory than in the clinic, likely because animal models incompletely reproduce human CIPN and because dosing and timing differ.

The authors are candid about limitations. Study heterogeneity in design, populations, and outcome measures precluded quantitative meta-analysis, several trials were small, and the restriction to English-language open-access studies published after 2019 may have introduced bias and excluded foundational duloxetine trials, which the authors discussed as context rather than primary evidence. Combination benefits remain hypothesis-generating, since most multimodal studies lacked appropriate comparator arms to disentangle whether effects are additive, synergistic, or driven by a single component. Prevention, too, remains unproven; current evidence supports antidepressants only for treating established CIPN. Still, the message for patients and clinicians is clear and cautiously optimistic: duloxetine stands as the first-line pharmacological option, topical amitriptyline deserves larger trials, and well-designed randomized studies of combination strategies could finally deliver the relief that millions of cancer survivors still lack.

Subject of Research: The efficacy of antidepressants, particularly duloxetine, in managing chemotherapy-induced peripheral neuropathic pain

Article Title: The Role of the Antidepressants in Managing Chemotherapy‐Induced Neuropathic Pain: A Systematic Review

Article References: Caminiti, R., Mazza, V., Nucera, S., Oppedisano, F., Passacatini, L. C., Maiuolo, J., Malafoglia, V., Giorgio, A., Soluri, A., Pileggi, C., Tomino, C., Mollace, V., Ilari, S., & Muscoli, C. (2026). The Role of the Antidepressants in Managing Chemotherapy‐Induced Neuropathic Pain: A Systematic Review. Pharmacology Research & Perspectives, 14(5), Article e70327. https://doi.org/10.1002/prp2.70327

Image Credits: AI Generated

DOI: 10.1002/prp2.70327

Keywords: chemotherapy-induced peripheral neuropathy, CIPN, duloxetine, antidepressants, neuropathic pain, systematic review, SNRI, amitriptyline, cancer survivors, pain management, mirogabalin, tapentadol