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ACP PUBLISHES MIGRAINE PREVENTION GUIDELINES

woman with migraine
The American College of Physicians (ACP) recently published migraine prevention guidelines. The recommendations are based on a systematic review and network meta-analysis that they performed and are intended for nonpregnant adults with episodic migraine (defined as 1 to 14 headache days per month). Key recommendations include:
  • First-line therapies: Beta-blocker (metoprolol or propranolol), valproate, venlafaxine, amitriptyline
  • Second-line therapies: CGRP receptor antagonists (atogepant, rimegepant) or CGRP antibodies (eptinezumab, erenumab, fremanezumab, or galcanezumab)
  • Third-line therapy: Topiramate

All of the guidelines are based on low-certainty evidence, as there are few meaningful head-to-head trials comparing migraine drugs. Their reasoning for recommending CGRP drugs over topiramate is that topiramate has a less favorable side effect profile.

Migraine prevention has always been the Wild West of pharmacotherapy, as a broad range of medications with seemingly unrelated mechanisms are used for treatment. Fortunately, most recommended drugs are affordable. The newer CGRP drugs are expensive and have modest efficacy in trials, reducing average migraine days per month by 1 - 2 compared to placebo. Notably, placebo typically performs well in migraine trials, likely reflecting overdiagnosis, as patients and some providers tend to label all headache syndromes as migraines.
New migraine therapies get hypertension and Raynaud's precautions
pills with warning
The FDA recently required that all calcitonin gene-related peptide (CGRP) antagonist therapies, including newer migraine therapies like Aimovig and Nurtec, add precautions about hypertension and Raynaud's phenomenon to their labeling. In postmarketing reports, worsening and new-onset hypertension have been reported in some patients treated with CGRP antagonist therapies. Likewise, new-onset and worsening Raynaud's phenomenon has also been observed. Patients receiving CGRP antagonists should monitor their blood pressure, especially during initiation, and consider discontinuation if significant increases are noted. Caution should be used when prescribing to patients with Raynaud's, and therapy should be discontinued for worsening or new-onset disease.

MALE-PARTNER TREATMENT DECREASES BACTERIAL VAGINOSIS RECURRENCE

picture of clue cells
Bacterial vaginosis (BV), affecting up to 30% of young women, has a high recurrence rate, with over 50% of women experiencing reinfection within 12 weeks. The cause of BV is poorly understood, but women who report sex with a regular partner have twice the risk of those who are not sexually active. This observation has led to speculation that the condition is sexually transmitted. However, previous studies where females and their male partners were treated with oral therapy have not demonstrated a reduction in recurrence. One possible explanation for these findings is that oral therapies alone may not be sufficient to clear cutaneous penile carriage of bacterial vaginosis–associated organisms. To test this theory, Australian researchers randomized monogamous couples in which the woman had BV to female-only treatment (female-only group) or female and male partner treatment (partner-treatment group). In both groups, females received metronidazole 400 mg twice daily for 7 days or intravaginal metronidazole or clindamycin if contraindicated. In the partner-treatment group, males received the same metronidazole regimen along with 2% clindamycin cream applied to the penile skin twice daily for 7 days. During follow-up, females were tested for BV at day 8, week 4, week 8, week 12, and as needed for symptoms. At study conclusion, the primary outcome, BV recurrence within 12 weeks, was significantly lower in the partner-treatment group compared to the female-only group (35% vs 63%, p<0.001)

This study provides some insight into BV and sexual transmission. It also raises the question of whether topical therapy alone in male partners, including over-the-counter creams like Neosporin, could reduce recurrence. Lastly, it's important to note that 35% of women in the partner-treatment group had a recurrence, suggesting that some type of underlying predisposition plays a significant role in BV susceptibility.

Journavx® (suzetrigine), new pain med with a novel mechanism
Journavx bottle
The FDA recently approved Journavx® (suzetrigine), a novel pain medication with a unique mechanism of action. Suzetrigine is a sodium channel blocker that selectively inhibits NaV1.8 voltage-gated sodium channels, which are expressed in peripheral sensory neurons involved in pain signaling. In a study of 1,118 patients undergoing abdominoplasty, suzetrigine demonstrated similar pain relief to hydrocodone/acetaminophen (5 mg/325 mg every 6 hours) over the first 48 postoperative hours. However, a separate similar study involving 1073 bunionectomy patients found suzetrigine to be superior to placebo but inferior to hydrocodone/APAP.

Suzetrigine's side effect profile is comparable to placebo, and no significant precautions have been identified. The recommended dosage is 100 mg once (on an empty stomach), followed 12 hours later by 50 mg every 12 hours (with or without food). Its use has not been studied beyond 14 days. Suzetrigine is a CYP3A substrate and inducer and should not be administered with strong CYP3A inhibitors. A notable interaction exists with hormonal contraceptives containing progestins other than levonorgestrel and norethindrone. The prescribing information advises that women taking these medications should use additional nonhormonal (e.g., condoms) or alternative contraceptives (e.g., combined oral contraceptives containing levonorgestrel or norethindrone) during treatment and for 28 days after discontinuation.

A novel, non-opioid pain reliever is a significant and much-needed addition. However, like all newly approved drugs, it is expensive and will likely face pushback from insurers. A study comparing it to a high-dose or potent NSAID, such as ketorolac, would be informative.

EXPERT GROUP RECOMMENDS AGAINST POPULAR PROCEDURES FOR CHRONIC SPINE PAIN

woman receiving spine injection
Spinal injections, frequently performed in pain medicine practices, are a common intervention for chronic back pain, with an estimated 9 to 11 million injections performed annually in the US alone. Despite their widespread use, studies examining their efficacy have been mixed, with placebo-controlled trials typically finding no effect. [PMID 21914755, PMID 24988555] To further explore the issue, the British Medical Journal convened a panel comprising four patients with chronic spine pain, 10 clinicians experienced in managing chronic spine pain, and eight methodologists. The group reviewed randomized controlled trials and observational studies involving spine procedures and issued the following recommendations:

  • The following procedures have no proven benefit and should not be offered for radicular or axial spine pain in the cervical or lumbar region:
    • Epidural injection of local anesthetic, steroids, or their combination
    • Joint radiofrequency ablation with or without joint targeted injection of local anesthetic plus steroid
    • Joint-targeted injection of local anesthetic, steroids, or their combination
    • Intramuscular injection of local anesthetic with or without steroids
    • Dorsal root ganglion radiofrequency with or without epidural injection of local anesthetic or local anesthetic plus steroids

These recommendations contradict those of the American Society of Interventional Pain Physicians (ASIPP), a professional organization that represents pain management physicians. The 2021 ASIPP guidelines strongly endorse spinal injections for treating chronic lumbar and cervical pain. In their discussion, the ASIPP authors argue that saline or short-acting local anesthetics, frequently used as controls in steroid injection studies, shouldn't be considered placebos because they have an actual therapeutic effect. They go on to contend that single-arm analysis (i.e., looking at therapies individually without comparing them to a control group) is most telling and should receive the majority of emphasis. Huh?

While it's a little comical and slightly disconcerting that a professional association would make an argument to disregard placebo controls in randomized trials, it's not surprising given that they represent doctors who put their kids through college performing these procedures. It also explains how two professional organizations can come to entirely different conclusions analyzing the same evidence. Like most things in life, all you have to do is follow the money.
Zoledronate infusion for fracture prevention in early postmenopausal women
Zoledronate, a bisphosphonate infusion approved to treat osteoporosis, has been shown to prevent fractures in women aged 65 and older with osteopenia (T-score -1 to -2.5). To explore its effects in younger women with bone loss in the osteopenia or less range, researchers randomized 1054 postmenopausal women aged 50 to 60 (average age 56) with a T-score between 0 and -2.5 at the lumbar spine, femoral neck, or total hip (average lumbar spine T-score: -0.43; average total hip T-score: -0.51) to one of three treatments: zoledronate 5 mg at baseline and in 5 years, zoledronate 5 mg at baseline and placebo in 5 years, or placebo at baseline and in 5 years. At 10 years, the primary outcome, morphometric vertebral fracture (fractures identified by their shape on X-ray as opposed to symptoms), occurred in 6.3% (Zoledronate-Zoledronate), 6.6% (Zoledronate-Placebo), and 11.1% (Placebo-Placebo) of patients (p<0.05). Incidences of any fracture were 24.7%, 27.4%., and 35.3%, respectively. (p<0.05). No cases of osteonecrosis of the jaw or atypical femoral fracture, two concerning bisphosphonate side effects, were reported during the trial.

Zoledronate reduced the 10-year fracture risk in postmenopausal women aged 50 to 60 with an average T-score of around -0.46. Two infusions were slightly more effective than one, and both were superior to placebo. A secondary analysis stratifying effect size by baseline bone mineral density (BMD) would have been informative but was not performed. With 45% of women aged 50 to 60 having T-scores less than 0, these results apply to a large population. Current USPSTF guidelines recommend BMD screening in women under 65 at increased risk of osteoporosis, which they loosely define as a 10-year fracture risk of 10% or more.

Providers wanting to incorporate this study into their practice could follow these steps:
  1. Screen postmenopausal women aged 50 to 60 with the FRAX tool
  2. If the 10-year risk of a major osteoporotic fracture is greater than 10%, order a BMD test
  3. If the T-score is 0 to -2.5 at the lumbar spine, femoral neck, or total hip, offer a one-time infusion of zoledronate 5 mg, with an anticipated effect of reducing the absolute risk of any fracture over 10 years by 8%

NEWS IN BRIEF

Saxenda for weight loss in children aged 6 to 12 years

Obese child holding gut
Approximately 21% of children aged 6 to 12 years in the U.S. are obese. Traditional weight-loss therapies, including intensive diet and exercise programs, have shown modest efficacy and limited long-term effects in trials. Saxenda (liraglutide), a once-daily GLP therapy approved for weight loss in adolescents and adults, was recently evaluated in children aged 6 to 12 years with obesity. The SCALE Kids study randomized 82 children (mean age 10) with an average BMI of 31 to Saxenda (target dose of 3 mg) or placebo. After 56 weeks, the primary outcome, percent change in BMI, was -5.8% in the Saxenda group and +1.6% in the placebo group (p<0.001). Percent increase in body weight also favored Saxenda (1.6% vs 10%, p=0.001). Eleven percent of Saxenda-treated patients discontinued therapy because of side effects.

While some providers may cringe at the idea of giving a 6-year-old a daily injection for weight loss, it's important to remember that there is a push in the medical community to recognize obesity as a chronic disease, rather than a lifestyle choice. If this is the case, these types of studies and treatments may become common.

Platelet-rich plasma (PRP) injections do not benefit trochanteric bursitis

woman receiving hip injection
Trochanteric bursitis, inflammation of the bursa located between the gluteal tendon and the lateral femur, affects up to 25% of women over the age of 50 and can be difficult to treat. Proponents of platelet-rich plasma (PRP) injections contend that the cytokine-rich solutions stimulate healing and reduce inflammation. To evaluate the effects of PRP injections on trochanteric bursitis, researchers randomized 79 patients with refractory trochanteric bursitis to ultrasound-guided leukocyte-rich PRP injections into the trochanteric bursa and gluteus medius, or placebo. After 12 months, there was no significant difference in a number of pain and function outcomes.

These results are not surprising given the lack of efficacy PRP injections have shown in other placebo-controlled trials. [PMID 34812863, PMID 31748208, PMID 34698782] A previous trochanteric bursitis study comparing steroid injections to physical therapy (PT) found that physical therapy was superior. [PMID 29720374] The PT regimen used in that study is available at the link below. Patients with trochanteric bursitis should skip the injections and focus on strengthening and exercise.

Study evaluates Wegovy for alcohol use disorder

passed-out man with liquor glass
Observational studies suggesting GLP-1 therapies may improve addictive behaviors, including alcoholism, have received significant press. To test these findings, researchers randomized 48 non-treatment-seeking adults with alcohol use disorder to semaglutide (max dose 1 mg weekly) or placebo. At 9 weeks, reductions in voluntary alcohol consumption, as observed in a controlled setting, were greater in the semaglutide group. However, semaglutide did not affect self-reported average drinks per calendar day or number of drinking days.

In this small study, semaglutide reduced the number of drinks consumed in a drinking episode but did not affect the number of drinking days. Study weaknesses include small sample size, missing data from participants who did not participate in the post-treatment session (N=16), and a moderate semaglutide dose. Additionally, outcomes were expressed as regression coefficients, and more intuitive measures (e.g., reduction in number of drinks) were not reported. While this study is encouraging, larger and longer trials are needed to define the role of GLP therapies in alcohol use disorder.

Study finds most children with appendicitis can be treated with antibiotics

pediatrician examining child with appendicitis
For over a century, the standard of care for appendicitis has been surgical appendectomy. However, recent studies have found that antibiotics effectively treat uncomplicated appendicitis in 60% to 70% of patients. Expanding on this evidence, a recent study in The Lancet randomized 936 children aged 5 - 16 with suspected non-perforated appendicitis to antibiotics or appendectomy. The primary outcome in the antibiotic group, appendectomy within 1 year, occurred in 34% of patients.

Similar findings have been observed in adults, including a study where subjects were treated with only 7 days of oral moxifloxacin. Patients with uncomplicated appendicitis who wish to avoid surgery can safely attempt an antibiotic-first approach, with the expectation that approximately 30% will eventually require an appendectomy.

POPULAR PAGES

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NEW DRUGS

POPULAR BUT UNPROVEN

  • Meniscal surgery - It's one of the most common orthopedic procedures performed, but does it do anything?
  • CPAP for sleep apnea - Sleep doctors are on every corner it seems, but what are the benefits of diagnosing and treating sleep apnea?
  • Knee injections - these treatments are popular among orthopedists and primary care doctors, but are they effective?
  • Pneumonia vaccines in adults - vaccine manufacturers, the CDC, and Medicare want everyone to get a pneumonia vaccine, so they must be highly effective, right?
COBENFY, A NEW ANTIPSYCHOTIC WITH A NOVEL MECHANISM
doctor writing prescription
For decades, dopamine antagonists have been the primary treatment for psychotic disorders like schizophrenia. While effective, these drugs can have significant side effects. First-generation drugs like haloperidol can cause extrapyramidal symptoms (EPS), while second-generation agents like risperidone are known to induce weight gain and hyperprolactinemia. These adverse effects often limit patient compliance, underscoring the need for alternative therapies. Cobenfy, a combination of xanomeline and trospium chloride, is the first non-dopamine antagonist antipsychotic approved to treat schizophrenia. Xanomeline is a muscarinic cholinergic receptor agonist that preferentially stimulates cerebral M1 and M4 receptors, which are involved in schizophrenia pathophysiology. Trospium is a peripheral-acting antimuscarinic agent included to mitigate xanomeline's cholinergic effects. Cobenfy's side effects are primarily gastrointestinal and include nausea (19%), dyspepsia (18%), constipation (17%), and vomiting (15%). It is contraindicated in patients with liver disease and conditions that may be exacerbated by trospium's anticholinergic effects (e.g., urinary retention, reduced GI motility). It comes in a capsule taken twice daily, at least one hour before or two hours after a meal, as food reduces its absorption by 90%.

Providers treating schizophrenia now have an alternative to dopamine antagonists, which have been the only option since the approval of chlorpromazine in 1954. In two studies (see links below), Cobenfy reduced the score on the Positive and Negative Syndrome Scale (range 30 - 210, with higher scores indicating worse symptoms) by 11 points more than placebo. Head-to-head studies with dopamine antagonists are needed to truly define Cobenfy's therapeutic value.


Zepbound and Wegovy in weight-related conditions
Woman injecting GLP weight-loss drug
With the publication of two recent Zepbound (tirzepatide) studies, GLP weight-loss drugs continue their streak of positive trials in obesity-related conditions. In the first study, Zepbound was compared to placebo in 731 patients with heart failure with preserved ejection fraction (HFpEF). After two years of follow-up, the absolute risk of a composite of death from cardiovascular causes or worsening heart failure was 5.4% lower in the Zepbound group (9.9% vs 15.3%). [Pubmed abstract] The second trial (N=1032), a substudy of the SURMOUNT-1 weight-loss trial, found that over 3.4 years, Zepbound significantly reduced the incidence of diabetes compared to placebo in individuals with prediabetes (1.3% vs 13.3%). [Pubmed abstract] These studies add to a growing list of trials, summarized below, where Zepbound and Wegovy (semaglutide) have been found to improve outcomes in obesity-related conditions.

  • Obstructive sleep apnea (OSA): In a 52-week trial enrolling overweight adults with OSA (N=469), Zepbound significantly reduced the apnea-hypopnea index, body weight, hypoxic burden, and systolic blood pressure compared to placebo. [Pubmed abstract] In December 2024, Zepbound received FDA approval for moderate to severe OSA in adults with obesity.
  • Nonalcoholic steatohepatitis (NASH): In a 52-week study (N=190) enrolling adults with NASH, more patients treated with Zepbound had NASH resolution compared to placebo (62% [15 mg dose] vs 10%) [Pubmed abstract]
  • Heart failure with preserved ejection fraction (HFpEF): Like Zepbound, Wegovy has also been shown to improve HFpEF. In a 52-week study (N=529) enrolling obese adults with HFpEF, Wegovy was superior to placebo for improving heart failure symptoms and physical endurance. [Pubmed abstract]
  • Secondary prevention of cardiovascular disease (CVD): In a 40-month study (N=17,604) enrolling overweight adults with a history of CVD, Wegovy was superior to placebo for reducing a composite of CVD events (6.5% vs 8%). [Pubmed abstract] Based on this study, Wegovy received FDA approval for the secondary prevention of CVD events.
  • Knee osteoarthritis (OA): In a 68-week study (N=407) enrolling obese adults with moderate knee OA, Wegovy was superior to placebo for improving knee pain. [Pubmed abstract]
  • Prediabetes: As discussed above, Zepbound was significantly better than placebo at preventing progression to diabetes over 3.4 years in participants with prediabetes (1.3% vs 13.3%). [Pubmed abstract]

To date, the FDA has granted two non-obesity indications for Zepbound and Wegovy: OSA for Zepbound and secondary prevention of CVD events for Wegovy. However, more are sure to come as these highly effective weight-loss drugs continue to change people's lives.

CLINICAL CHALLENGE

A 45-year-old female comes to see you for her annual physical. She reports having gastric bypass surgery three years ago and says she followed up with her surgeon once and never went back. She asks you to order her routine lab work.

Given her history of gastric bypass, what lab work is recommended? Are any other studies indicated? Find out at the link below.