Contributed by: Anuolu Bank-Oni, PharmD, CDE, BCGP

As defined by the National Institute for Health and Care Excellence (NICE) guideline, chronic primary pain is present in one or more parts of the body and lasts for more than three months. Chronic pain negatively impacts the physical, emotional, and social well-being of the patient. The economy also shares in the burden, as chronic pain increases healthcare costs while reducing work productivity.

Treating chronic pain can be challenging because each patient requires a tailored care plan. Finding the balance between the benefits and risks of available treatment options requires the collaboration of the physician and the patient. The physician should ensure the patient actively participates in creating their treatment plan.

NICE recently published draft guidance on the assessment and management of chronic pain in patients aged 16 years and older.

Non-pharmacological management of chronic primary pain

Supervised group exercise, acceptance and commitment therapy (ACT) or cognitive behavioural therapy (CBT) are recommended for patients with chronic primary pain. Acupuncture or dry needling may be considered but more research is required to determine long-term benefits.

The guideline does not recommend biofeedback or electrical therapies (TENS, ultrasound and interferential therapy). Manual therapy requires additional research, as there is insufficient evidence to issue a recommendation regarding its use.

Pharmacological management of chronic primary pain

The guideline recommends against the use of most of the currently prescribed pain medications, by any route, to patients aged 16 years and older to manage chronic primary pain. These include:

• antiepileptics including gabapentinoids, (except when gabapentinoids are prescribed as part of a clinical trial for complex regional pain syndrome)
• antipsychotics
• benzodiazepines
• corticosteroids
• ketamine
• local anaesthetics (except as part of a clinical trial for complex regional pain syndrome)
• local anaesthetic/corticosteroid combinations
• non-steroidal anti-inflammatory drugs (NSAIDs)
• opioids
• paracetamol

According to NICE, studies showed that these medications have limited/no benefit in managing chronic primary pain. Conversely, there was an increased risk of addiction and misuse with opioids, benzodiazepines, gabapentinoids. Other adverse effects observed include gastrointestinal bleeds with NSAID, and impaired psychological and physical functioning with benzodiazepines.

Instead, antidepressants (duloxetine, fluoxetine, paroxetine, citalopram, sertraline or amitriptyline) are listed as therapeutic options, recognising this would be off-label use. Benefits and risks should be discussed with the patient.

Studies indicate that antidepressants improve quality of life, pain and psychological distress compared with placebo. However, most of the evidence available involved women with fibromyalgia.

It is important to remember that patients who discontinue antidepressants, opioids, gabapentinoids or benzodiazepines may experience withdrawal symptoms. NICE is developing a guideline on withdrawal management.

Patients who are currently on any of these medications should be educated on the most recent available evidence. Physicians should discuss the risks associated with continuing the medications and possible alternatives.

Conclusion

Chronic primary pain affects a significant portion of the population and poses a burden to patients and the community. Long term, deprescribing will reduce the risk of adverse effects and promote the appropriate use of medications. More research is required to determine the most appropriate treatment options for chronic primary pain.

Reference

1. Chronic pain: NICE guideline DRAFT (August 2020). [online] Available at: <https://www.nice.org.uk/guidance/gid-ng10069/documents/draft-guideline> [Accessed 11 August 2020]

There is evidence of an independent, dose-response relationship between the use of anti-secretory medications and COVID-19 positivity; individuals taking PPIs twice daily have higher odds for reporting a positive test when compared to those using PPIs up to once daily, and those taking the less potent H2RAs are not at increased risk. This is the finding of an observational study published in The American Journal of Gastroenterology, July 7, 2020. The online survey enrolled 53,130 adults.

Previous study has shown that pH ≤3 impairs the infectivity of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1). Based on the findings of the current study, this appears to be the case for SARS-CoV-2.

According to the study authors, because SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor to invade and rapidly replicate in enterocytes, an increase in gastric pH >3 due to the use of PPIs could allow it to more easily enter the gastrointestinal tract, which would lead to enteritis, colitis and systemic spread to other organs, including the lungs.

Information Sheet and FAQs About Proton Pump Inhibitors (PPIs) and Risk of COVID-19

Members of the American College of Gastroenterology (ACG) leadership team partnered with the study authors to prepare a brief overview of the research, discuss its findings, and address potential implications for clinical care.

The group addressed the following questions:

1. What are the main results of the study?
2. Do patients need to stop their PPIs right now because of this study?
3. How might you use the results of this study to advise patients taking PPIs?
4. Why was this study performed?
5. What are the limitations of the study?

Click here for details: https://webfiles.gi.org/

Sources:

1. Almario CV, Chey WD, Spiegel BMR. Increased risk of COVID-19 among users of proton pump inhibitors. Am J Gastroenterol 2020. Available online: https://journals.lww.com/ajg/Documents/AJG-20-1811_R1(PUBLISH%20AS%20WEBPART).pdf
2. The American Journal of Gastroenterology. Information Sheet and FAQs About Proton Pump Inhibitors (PPIs) and Risk of COVID-19. Available online: https://webfiles.gi.org/links/media/ACG_Almario_et_al_Info_Sheet_and_FAQs_About_PPIs_COVID19_07072020_FINAL.pdf

[FDA Update, July 13, 2020] – FDA is alerting patients and health care professionals to several voluntary recalls of extended-release (ER) metformin due to possible contamination with nitrosodimethylamine (NDMA) above the acceptable intake limit.

Note that FDA testing has not shown NDMA in immediate-release (IR) metformin products (the most commonly prescribed type of metformin).

IMPORTANT LINKS

Search database of recalled metformin products: https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-metformin-products

QA on NDMA impurities in metformin products: https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-metformin-products

Information about nitrosamine impurities in medications: https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications

Contributed by: Dr. Collins E. M. Okoror, MBBS (Ib), MBA, PDip (HRM), FWACS (OBGYN), FMCOG, MPH (RFH)

Consultant Obstetrician and Gynaecologist

Combined oral contraception (COC)

The COCs are an effective form of contraception combining the effect of both the progesterone and oestrogen hormones. Basically, they exhibit their contraceptive effects by inhibiting ovulation, thickening of the cervical mucus and thinning of the endometrium. They should be taken for consecutive days at about the same time of the day. Various forms are available at different proportions of the hormones.

COC containing ≤30 µg of ethinylestradiol (EE) with levonorgestrel (LNG) or noresthisterone (NET) is considered the first choice. Microgynon, a 2nd generation COC, containing 30 µg of EE and 150 µg of LNG, has become the first choice in women requesting COCs.

The second line 2nd generation COC pills include:

• Low strength NET and EE e.g. Loestrin,
• Standard strength NET and EE e.g. Brevinor, and
• Phased COC EE and LNG e.g. Logynon.

The 3rd generation COCs have an increased risk of venous thromboembolism, patients should be assessed and counselled for this when they are being considered. They contain standard strength and low strength of desogestrel (DSG) and EE as first and second lines, respectively. Examples

• Standard strength e.g. Marvelon, Desofem (DSG 150 µg & EE 30 µg)
• Low strength e.g. Mercilon (DSG 150 µg & EE 20 µg).

Initiating COCs

The COCs are best started within the day 1–5 of the cycle. When started after day 5, an additional barrier method of contraception should be used for the first 7 days of initiation. Pregnancy test should be done after 3 weeks if unprotected sexual intercourse (UPSI) has occurred since the last period or if a woman who is amenorrhoeic and with negative pregnancy test has had UPSI in the last 3 weeks.

Switching pills

It is not uncommon to switch pills for perceived or actual adverse effects. Some of the conditions necessitating pills switch include:

Breakthrough bleeding – Before switching brand, check for compliance, exclude pregnancy, drug-drug interaction, infection and local causes of bleeding per vaginam. A switch should be made to the standard strength 2^nd generation COC or the 3^rd generation COC when the earlier is not available or to the triphasic COC when the earlier two are not available.

Nausea or headache – Pregnancy and eye pathologies should be excluded in these circumstances before switching brands. Where appropriate, a switch should be made to the low strength 2^nd generation COC or the low strength 3^rd generation COC where the earlier is not available.

Acne, bloatedness, or breast tenderness – A switch should be to the standard strength 3^rd generation COC. Where this is unavailable or inappropriate, the client should be referred to the doctor for further evaluation.

Weight gain – Clients should be offered general advice on diet, exercises and being healthy. Where a switch is necessary, it should be to the standard strength 3^rd generation COC.

Reduced libido – This may be psychological (e.g., relationship issues, less motivation) and should necessitate a referral to the doctor for evaluation.

Mood swings – Take medical history to determine if the patient is experiencing mood changes all the time or in relation to withdrawal bleed. If it is ascertained that the mood swings are caused by the Microgynon after detailed history, a switch should be made to standard strength 3^rd generation COC.

Switching to another brand

When switching pills, the hormone-free interval (HFI) should be omitted, and the new pills commenced the next day i.e. day 22 of the previous pills or within day 1–2 of HFI. If 3–7 hormone-free pills or days are taken, the new brand should be commenced with barrier methods for the first 7 days. It is important to carry out a thorough evaluation of the client before considering a switch to another brand of COC.

Switching to progesterone-only pill (POP)

When switching from COC to POP, it should be started without a break within the day 1–2 HFI or during week 2–3 of COC. When the switch is necessary during week 1 of COC or day 3-7 HFI and in absence of UPSI since start of HFI, additional barrier method should be used for 2 days.

Progesterone-only pills (POP)

The progesterone only contraceptive pills are effective alternatives for clients in whom the oestrogen effects of the COC are undesirable or contraindicated and have no contraindication to the POPs. They have similar mechanisms of action with COC, though at varying degrees. Various forms are available, but the common ones are the NET 350 µg, LNG 30 µg and DSG 75 µg. While NET and LNG administration allows for a 3-hour missed pill window, DSG POP allows a window of 12 hours and is therefore, an option for those who have trouble in complying with stricter dosage regimen of other POPs.

Initiating POP

Like the COC, it is best taken daily at the same time each day beginning from day 1–5 of the cycle. When started after day 5, an additional barrier method of contraception should be used for the first 2 days of initiation. Pregnancy test should be done after 3 weeks if UPSI has occurred since the last period or if a woman who is amenorrhoeic and with a negative pregnancy test has had UPSI in the last 3 weeks.

References

1. Faculty of Sexual and reproductive Healthcare (FSRH). Combined hormonal contraception. London, UK: Clinical Effectiveness Unit, FERH; January 2019 (amended July 2019).
2. Faculty of Sexual and Reproductive Healthcare (FSRH). Progestogen-only pills. London, UK: Clinical Effectiveness Unit, FSRH; March 2015 (amended April 2019).
3. Telford and Wrekin Clinical Commissioning Group. Guidelines for initiation and switching of combined oral contraception. Telford, UK: Telford and Wrekin CCG; December 2016. Available at: https://www.telfordccg.nhs.uk/your-health/medicines-management/prescribing-guidelines/sexual-health-1/2242-oral-contraception-flowchart-and-guidance-v2/file

[WHO News release, June 16, 2020] – The World Health Organization (WHO) welcomes the initial clinical trial results from the United Kingdom (UK) that show dexamethasone, a corticosteroid, can be lifesaving for patients who are critically ill with COVID-19. For patients on ventilators, the treatment was shown to reduce mortality by about one third, and for patients requiring only oxygen, mortality was cut by about one fifth, according to preliminary findings shared with WHO.

The benefit was only seen in patients seriously ill with COVID-19, and was not observed in patients with milder disease. 

“This is the first treatment to be shown to reduce mortality in patients with COVID-19 requiring oxygen or ventilator support,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “This is great news and I congratulate the Government of the UK, the University of Oxford, and the many hospitals and patients in the UK who have contributed to this lifesaving scientific breakthrough.”

Dexamethasone is a steroid that has been used since the 1960s to reduce inflammation in a range of conditions, including inflammatory disorders and certain cancers. It has been listed on the WHO Model List of Essential Medicines since 1977 in multiple formulations, and is currently off-patent and affordably available in most countries.

The researchers shared initial insights about the results of the trial with WHO, and we are looking forward to the full data analysis in the coming days. WHO will coordinate a meta-analysis to increase our overall understanding of this intervention. WHO clinical guidance will be updated to reflect how and when the drug should be used in COVID-19.

Source:

WHO News release, June 16, 2020

Contributed by: Anuolu Bank-Oni, PharmD, CDE, BCGP

Childhood depression can have long-lasting developmental consequences on mental and physical health. Whereas cognitive behavioural therapy and fluoxetine are currently recommended for adolescents with moderate to severe depression, evidence is lacking in regard to treatment of children.

The Agency for Healthcare Research and Quality published a systematic review evaluating the efficacy and safety of nonpharmacological, pharmacological, and combination interventions for child (age range: 7 – 12 years) and adolescent (age range: 12 – 18 years) depressive disorders (major depressive disorder [MDD], persistent depressive disorder [PDD], and depressive disorder not otherwise specified [DD NOS]).

A search of MEDLINE, the Cochrane Library, the Cochrane Central Trials Registry, the Cumulative Index to Nursing and Allied Health Literature, and PsycINFO databases for all trials published up to May 29, 2019 produced 874 studies which were then screened. Of these, 60 studies were deemed eligible for analysis. Approximately 77% of the studies involved paediatric patients with a confirmed diagnosis of MDD only, while the remaining studies included a range of depressive disorders (MDD, PDD, DD NOS, or combinations).

The data revealed the following:

• In paediatric (children and adolescent) patients, psychotherapy (CBT or family therapy) may improve depressive symptoms, response, and functional status. No adverse events were reported with psychotherapy.
• A combination of medication plus psychotherapy may improve depressive symptoms, remission, and functional status when compared with psychotherapyalone.
• CBT and combination therapy (e.g. CBT plus fluoxetine) may be beneficial in patients with comorbid attention deficit hyperactivity disorder (ADHD).
• Selective serotonin reuptake inhibitors (SSRIs) may improve response and functional status in patients with MDD.
• For adolescents with MDD, there is an increased risk of serious adverse events, including suicidal ideation, with SSRIs. The risk of withdrawals due to adverse events is also increased. Paroxetine was noted as having an increased risk of suicidal ideation. Other SSRIs may have similar concerns, but there were insufficient data available. The Food and Drug Administration (FDA) has issued warnings on the suicide risk associated with SSRI use in pediatrics.
• For adolescents with MDD, escitalopram, fluoxetine, CBT, and combination therapy (fluoxetine plus CBT) may improve symptoms.
• The analyses found no evidence of benefit with serotonin and norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), and monoamine oxidase inhibitors (MAOI).

Available evidence is focused on treating adolescents with MDD. Additional research is needed to better understand appropriate treatment regimens for children, depressive disorders other than MDD, and the long-term effects of these interventions.

Reference:

• Viswanathan M, Kennedy SM, McKeeman J, et al. Treatment of Depression in Children and Adolescents: A Systematic Review [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2020 Apr. (Comparative Effectiveness Review, No. 224.) Evidence Summary

[FDA News Release, May 28, 2020] – The U.S. FDA has announced that several brands of metformin have tested positive for unsafe levels of the nitrosamine impurity, N-Nitrosodimethylamine (NDMA). NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests.

The agency has directed 5 companies to begin voluntary recall of the affected metformin extended-release (ER) formulations. The affected companies and metformin products are published on FDA’s website.

FDA is advising patients to continue taking metformin tablets even after recalls occur, until they consult with their health care professional who can prescribe a replacement. Patients with type 2 diabetes could face dangerous health risks if they stop taking their prescribed metformin.

Healthcare professionals should continue to prescribe metformin when clinically appropriate; FDA testing has not shown NDMA in immediate-release (IR) metformin products (the most commonly prescribed type of metformin). The agency is working with manufacturers of the recalled tablets to identify the source of the NDMA impurity. At this time, the elevated levels of NDMA have been found in some finished-dose tablets of the ER formulation but have not been detected NDMA in samples of the metformin active pharmaceutical ingredient.

Health Canada Important Safety Information, March 11, 2020

Earlier in Canada, certain lots of metformin have also been recalled due to the presence or possible presence of a nitrosamine impurity called N-Nitrosodimethylamine (NDMA) above the acceptable limit:

February 5, 2020 – Apotex Inc. recalled 8 lots of the diabetes medication APO-Metformin ER (extended release) 500 mg tablets

February 26, 2020 – Ranbaxy Pharmaceuticals Canada Inc. recalled six lots of its prescription RAN-Metformin drug from the Canadian market.

March 11, 2020 – JAMP Pharma Corporation voluntarily recalled all 26 lots of its prescription Metformin drug from the Canadian market (Metformin DIN 02380196 [500mg] and Metformin DIN 02380218 [850mg]) as a precautionary measure. NDMA test results are not available for this product; this recall has been initiated because of the potential presence of nitrosamine impurities in the finished product.

Details of the recalled metformin products are published on Health Canada website.

Sources:

1. FDA News Release, May 28, 2020
2. Health Canada Important Safety Information, March 11, 2020

[FDA News Release, May 29, 2020] – The U.S. Food and Drug Administration today granted approval to ORIAHNN™ (an estrogen and progestin combination product consisting of elagolix, estradiol and norethindrone acetate) capsules, co-packaged for oral use, for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

Oriahnn is the first FDA-approved non-surgical, oral medication option for the management of heavy menstrual bleeding associated with uterine fibroids in pre-menopausal women

Uterine fibroids, also called leiomyomas, are estrogen and progesterone-dependent non-cancerous tumors of the uterus and are the most common type of benign tumor in women of reproductive age, affecting up to 70 percent of Caucasian women and up to 80 percent of African American women by age 50. Fibroids can cause heavy menstrual bleeding, pain, bowel or bladder problems and infertility; some women may not experience any symptoms. They typically resolve after menopause but are a leading reason for hysterectomy (surgical removal of the uterus) in the United States when they cause severe symptoms.

Oriahnn may cause bone loss over time, and the loss in some women may not be completely recovered after stopping treatment. Because bone loss may increase the risk for fractures, women should not take Oriahnn for more than 24 months. Health care professionals may recommend a bone density scan (called DXA scan) when starting women on Oriahnn and periodically while on treatment.

The most common side effects of Oriahnn were hot flushes (sudden feelings of warmth), headache, fatigue and irregular vaginal bleeding. The drug label for Oriahnn includes a Boxed Warning about the risk of vascular events (strokes) and thrombotic or thromboembolic disorders (blood clots), especially in women at increased risk for these events. Patients should stop Oriahnn if a blood clot, heart attack or stroke occurs. Oriahnn is contraindicated (not to be used under any circumstance) in women with a history of or current blood clots and in women at increased risk for blood clots, including women over 35 years of age who smoke or women with uncontrolled hypertension. Other contraindications include known osteoporosis, a history of or current breast cancer or other hormonally sensitive cancer, liver disease or undiagnosed abnormal uterine bleeding.

Oriahnn does not prevent pregnancy. Women should use non-hormonal contraception during treatment and for one week after discontinuing the medication. Oriahnn may delay the detection of a pregnancy because it changes menstrual bleeding patterns. Oriahnn may increase blood pressure, which should be monitored in women with controlled hypertension during treatment with Oriahnn. Patients should be advised on signs and symptoms of liver injury. Patients are advised to seek medical attention if they experience suicidal ideation or behavior, new onset or worsening depression, anxiety or other mood changes. Patients taking Oriahnn may experience hair loss (alopecia). There is a risk of allergic reaction with Oriahnn because its inactive ingredient, FD&C Yellow No. 5 (tartrazine) may cause allergic-type reactions (including bronchial asthma) in some women.

Sources:

1. FDA News Release, May 29, 2020
2. AbbVie Press Release, May 29, 2020
3. Oriahnn full prescribing information

[FDA News Release, May 26, 2020] – The U.S. Food and Drug Administration (FDA) has approved artesunate for injection to treat severe malaria in adult and pediatric patients. Treatment of severe malaria with intravenous (IV) artesunate should always be followed by a complete treatment course of an appropriate oral antimalarial regimen.

In Nigeria, the antimalarial medicine recommended for the treatment of severe malaria is injectable (IV/IM) Artesunate. Where this is not readily available, intramuscular artemether or intravenous/ intramuscular quinine can be used as alternatives.

(Nigeria’s National Guidelines for Diagnosis and Treatment of Malaria, 3rd ed. Federal Ministry of Health National Malaria and Vector Control Division, Abuja-Nigeria, May 2015)

Prior to this approval, IV artesunate was only available to patients through the FDA’s Expanded Access program, which allowed the U.S. Centers for Disease Control and Prevention (CDC) to provide IV artesunate to U.S. patients with severe malaria and to patients with uncomplicated malaria who are unable to take oral medications under an investigational new drug (IND) protocol. There has been no FDA-approved drug for treatment of severe malaria in the United States since the marketing of quinine was discontinued by the manufacturer in March 2019.

The safety and efficacy of IV artesunate for the treatment of severe malaria was primarily evaluated in a randomized controlled trial in Asia (Trial 1) and a supportive published randomized controlled trial in Africa (Trial 2).

Trial 1 enrolled 1,461 patients who received either IV artesunate or the comparator drug quinine and included 202 pediatric patients younger than 15 years. Trial 2 included 5,425 randomized pediatric patients younger than 15 years of age with severe malaria who were treated with artesunate or quinine. In both trials, the number of patients treated with artesunate who died in the hospital was significantly lower than the number who died in the control group treated with quinine.

In Trial 1, the most common adverse reactions in patients with malaria treated with IV artesunate were acute renal failure requiring dialysis, hemoglobinuria, and jaundice. The safety profile in Trial 2 was generally similar to Trial 1.

Artesunate should not be used in patients with known serious allergy to artesunate such as anaphylaxis.

Source: FDA News Release, May 6, 2020

[Evofem News Releases, May 22, 2020] – Evofem Biosciences, Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved Phexxi™ (lactic acid, citric acid and potassium bitartrate) vaginal gel for the prevention of pregnancy in females of reproductive potential for use as an on-demand method of contraception.

Phexxi is the first non-hormonal, on-demand, vaginal pH regulator (VPR) contraceptive designed to maintain vaginal pH within the normal range of 3.5 to 4.5 – an acidic environment that is inhospitable to sperm.

“There have been a limited number of advances in birth control over the last two decades; Phexxi represents an important step forward in women’s health,” said Michael A. Thomas, M.D., Chair of the Department of Obstetrics and Gynecology at the University of Cincinnati College of Medicine.  “Many of my patients have cycled through numerous contraceptive options and still have not found the right fit for their sexual and reproductive needs. Phexxi offers women freedom from hormones and control over how they choose to prevent pregnancy. I look forward to offering this new on-demand option to my patients.”

IMPORTANT SAFETY INFORMATION

Indications and usage

Phexxi™ is indicated for the prevention of pregnancy in females of reproductive potential for use as an on-demand method of contraception.

Limitations of use

Phexxi™ is not effective for the prevention of pregnancy when administered after intercourse.

Warnings and precautions

Few cases (0.36%) of adverse reactions of cystitis, pyelonephritis and other upper urinary tract infection (UTI) have been reported in Phexxi™ clinical studies. Of these, one case of pyelonephritis was considered serious and required hospitalization. Avoid use of Phexxi™ in females of reproductive potential with history of recurrent urinary tract infection or urinary tract abnormalities.

Adverse reactions

Most common adverse reactions (≥2%) were vulvovaginal burning sensation, vulvovaginal pruritus, vulvovaginal mycotic infection, urinary tract infection, vulvovaginal discomfort, bacterial vaginosis, vaginal discharge, genital discomfort, dysuria, and vulvovaginal pain.

Patients should be counseled on the following:

• To contact and consult their healthcare provider for severe or prolonged genital irritation or experiencing urinary tract symptoms.
• To discontinue Phexxi™ if they develop a local hypersensitivity reaction.
• That Phexxi™ does not protect against HIV infection or other sexually transmitted infections.

Sources:

1. FDA-Approved Label for Phexxi®
2. Full Prescribing Information for Phexxi® is available at Phexxi.com
3. Evofem Press Release, May 22, 2020