James A. Simon, MD, CCD, NCMP, FACOG of George Washington University School of Medicine, and others evaluated the risk of venous thromboembolism (VTE) and cardiovascular disease (CVD) complications, and assessed healthcare costs in menopausal women using an estradiol transdermal system versus oral estrogen therapy (ET).

   Health insurance claims from 60 self-insured US companies from 1999 to 2011 were analyzed. Women at least 50 years of age, newly initiated on transdermal or oral ET, were included. Cohorts were matched 1:1 based on exact factors and propensity score-matching methods. The incidence rate ratios (IRRs) of CVD complications, as well as VTE and other CVD events separately, were assessed through conditional Poisson models. Cohorts were also compared for healthcare costs using linear regression models to assess per-patient per-month cost differences. Confidence intervals (CIs) and P values were determined using a nonparametric method for cost outcomes.

   Transdermal ET users also incurred lower adjusted all-cause and VTE/CVD-related healthcare costs relative to oral ET users and transdermal users also incurred lower healthcare costs.

     Metformin is considered a first-line treatment in the management of insulin resistance and type 2 diabetes mellitus. Metformin can also decrease triglyceride levels and has also been associated with a modest weight loss. Adverse side effects are frequent in patients taking metformin; the most notable being gastrointestinal reactions in up to 20% of patients taking oral metformin, including anorexia, nausea, vomiting, abdominal discomfort, gas, bloating and diarrhea. The effects are dose related and up to 5% of patients will discontinue oral metformin therapy due to the side effects. 77% of patients taking metformin will also develop a vitamin B 12 deficiency, which has been associated with peripheral neuropathy.

   The bioavailability of oral metformin is only 50-60% under fasting conditions. Food delays the absorption. Gastrointestinal side effects frequently lead patients to not take metformin on an empty stomach, further reducing the bioavailability. Orally administered metformin is degraded in the GI tract.

   Transdermal metformin has been studied as an alternative treatment in patients with insulin resistance who are unable to tolerate oral medications. One advantage of using transdermal metformin is that it bypasses the gastrointestinal system, and therefore does not produce the gastrointestinal side effects associated with oral metformin. Transdermal metformin is dosed at only 5-10% of the typical oral dose, and this significantly reduced actual dose has achieved effects that are clinically comparable to the typical oral dose. Reduced incidence of adverse effects has improved compliance and tolerability for patients who have difficulty swallowing oral agents.

   In clinical use of transdermal delivery of metformin formulated with Pluronic Lecithin Organogel (PLO), it was observed that approximately 5-10% of the amount of the usual oral dose elicited a therapeutic response in terms of decreased blood-glucose levels. For example, if a patient was taking 1000 mg of metformin by mouth twice daily, an equivalent transdermal preparation would be 50 to 100 mg transdermally twice daily. This can be achieved by the patient applying as little as 0.5 ml (50mg) of metformin 10%  transdermal gel applied to the skin twice daily.  In other words, the amount of metformin as an active pharmaceutical ingredient administered transdermally is usually only 25-100 mg twice daily. Therefore, it is important that patients are carefully monitored during changes in medication. Transdermal metformin is recommended only for patients with stable, controlled blood sugar and optimized HgA1C levels.

   Disrupted and nonrestorative sleep is widely thought to play a role in the pathophysiology of FM, suggesting that treatments that improve sleep quality would address global symptoms that patients with FM experience. A randomized, double-blind, placebo-controlled trial included 205 participants who met the 2010 American College of Rheumatology (ACR) diagnostic criteria for FM. Researchers found that a rapidly absorbed proprietary eutectic sublingual tablet formulation of low-dose (2.8 mg) cyclobenzaprine HCl taken at bedtime for 12 weeks improved both sleep and patient outcomes related to pain and other measurements. Phase 2b of this study (BESTFIT) was conducted at 17 U.S. sites.

      Complex Regional Pain Syndrome (CRPS), formerly known as Reflex Sympathetic Dystrophy (RSD), is a neuropathic pain syndrome that is characterized by a combination of sensory, autonomic, vasomotor, and motor dysfunctions, with pain that is out of proportion to the initial injury. Diagnoses of CRPS are often delayed because it is under-recognized. CRPS involves glial activation and central sensitization in the central nervous system. If appropriate treatments are started early enough in progression of the disease, there is reduced chance for the spread of regional pain, autonomic dysfunction, motor changes, and negative sensory symptoms. As CRPS progresses, it becomes refractory to sympathetic nerve blocks, conventional analgesics, anticonvulsants and anti-depressants. Low-dose naltrexone (LDN) refers to doses approximately 50-fold lower than doses of naltrexone typically given to patients addicted to opioids. Low-dose naltrexone (LDN) is known to antagonize the Toll-like Receptor 4 (TLR4) pathway and attenuate activated microglia.

    Chopra and Cooper of the Department of Medicine, Alpert Medical School of Brown University, reported positive outcomes for two CRPS patients after they were treated with low-dose naltrexone (LDN) in combination with other CRPS therapies. Prominent CRPS symptoms, including dystonic spasms and fixed dystonia, remitted in both patients following treatment with LDN after conventional CRPS pharmacotherapy failed to suppress their recalcitrant CRPS symptoms.

   In Case 1, a 48 year-old male sustained an injury to his right leg in 2006. By 2007, the patient developed moderate CRPS symptoms in his upper extremities. In 2008, he developed blisters and skin ulceration on his right leg. By 2009, he developed muscle spasms in the right arm. In 2010, he underwent a cardiac bypass surgery for coronary artery disease. His CRPS symptoms became widespread after this surgery and by 2011, he developed significant dystonic spasms to both arms, resulting in hyperextension of his fingers. From 2008 to 2012, the patient underwent multiple treatments with anticonvulsants, antidepressants, physical therapy, psychotherapy, topical and systemic analgesics, including but not limited to opioids. In August of 2011, the patient began low-dose intravenous ketamine infusions every 4 to 6 weeks. In January 2012, his use of oxycodone was changed to tapentadol. This narcotic was removed one week prior to starting LDN 4.5 mg once per day at night. By March 2012, the patient's requirements for ketamine infusions were less frequent and he recovered from CRPS flares more quickly, felt more energetic, and tolerated pain better. He became physically more active, and his sleep improved significantly. Within 2 months after starting LDN, the patient's dystonic spasms discontinued, although he still had moderate pain in both arms. The patient was able to walk without a cane which he had used continuously since 2006. His pain on the Numeric Rating Scale was 8-10 before starting LDN and dropped to 5-6 with LDN therapy. No side effects of LDN were noted.

   Glial attenuators such as LDN are likely to provide benefits in controlling CNS neuroinflammation that arises from peripheral nerve injury, CNS injury, or autoimmune attack on CNS targets. However, it is possible that inhibiting CNS neuroinflammation with glial attenuators might be deleterious to individuals who are immuno-compromised  or have an ongoing viral or bacterial infection.