Céline Villier

The nocebo effect of drugs.

While the placebo effect has been studied for a long time, much less is known about its negative counterpart, named the nocebo effect. However, it may be of particular importance because of its impact on the treatment outcomes and public health. We conducted a review on the nocebo effect using PubMed and other databases up to July 2014. The nocebo effect refers by definition to the induction or the worsening of symptoms induced by sham or active therapies. Examples are numerous and concerns both clinical trials and daily practice. The underlying mechanisms are, on one hand, psychological (conditioning and negative expectations) and, on the other hand, neurobiological (role of cholecystokinin, endogenous opioids and dopamine). Nocebo effects can modulate the outcome of a given therapy in a negative way, as do placebo effects in a positive way. The verbal and nonverbal communications of physicians contain numerous unintentional negative suggestions that may trigger a nocebo response. This raises the important issue of how physicians can at the same time obtain informed consent and minimize nocebo‐related risks. Every physician has to deal with this apparent contradiction between primum non nocere and to deliver truthful information about risks. Meticulous identification of patients at risk, information techniques such as positive framing, contextualized informed consent, and even noninformation, is valuable.

Toxicité cardiaque du polidocanol : rapport d’un cas et revue de la littérature

OBJECTIVE Polidocanol foam sclerotherapy is a treatment of symptomatic venous disease. This solution is highly valued by clinicians because of its high efficacy and excellent safety profile. Systemic adverse effects are rare. Some life-threatening reactions have been reported. We report a case of respiratory and cardiac arrest, and a literature review on the cardiac toxicity of polidocanol used within and outside their licensed indications. MAIN OUTCOME MEASURES A 48-year-old woman, with a symptomatic venous disorder, CEAP grade C2, was treated by echosclerotherapy for a great saphenous vein. She developed a malaise and respiratory and cardiac arrest occurred within minutes after a 7 ml foam polidocanol injection. Cardiopulmonary resuscitation was immediately started before restoration of pulses. A literature search was done using the Medline database. RESULTS Five cases of cardiac toxicity were reported with polidocanol, but four of them were used outside their licensed indications. Because of the very suggestive chronology and the lack of any other obvious etiology, this cardiac arrest was attributed to polidocanol. Initial ST-segment elevation and negativity of anaphylaxis markers suggest a direct myocardial toxicity. CONCLUSIONS Clinicians should be aware of the possibility of little-known but potentially serious cardiac adverse reaction with polidacanol injection and be prepared to initiate cardiopulmonary resuscitation if needed.

Symptomatic Hypoglycemia Associated with Trimethoprim/Sulfamethoxazole and Repaglinide in a Diabetic Patient

Objective To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient. Case summary A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous d-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale). Discussion This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia. Conclusions This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.

Impact of concomitant medications on obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is characterized by repeated episodes of apnoea and hypopnoea during sleep. Little is known about the potential impact of therapy drugs on the underlying respiratory disorder. Any influence should be taken into account and appropriate action taken, including drug withdrawal if necessary. Here, we review drugs in terms of their possible impact on OSA; drugs which (1) may worsen OSA; (2) are unlikely to have an impact on OSA; (3) those for which data are scarce or contradictory; and (4) drugs with a potentially improving effect. The level of evidence is ranked according to three grades: A – randomized controlled trials (RCTs) with high statistical power; B – RCTs with lower power, non‐randomized comparative studies and observational studies; C – retrospective studies and case reports. Our review enabled us to propose clinical recommendations. Briefly, agents worsening OSA or inducing weight gain, that must be avoided, are clearly identified. Drugs such as ‘Z drugs’ and sodium oxybate should be used with caution as the literature contains conflicting results. Finally, larger trials are needed to clarify the potential positive impact of certain drugs on OSA. In the meantime, some, such as diuretics or other antihypertensive medications, are helpful in reducing OSA‐associated cardiovascular morbidity.

Drug-induced Raynaud's phenomenon: beyond β-adrenoceptor blockers

AIM Drug-induced Raynauds phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Drug‐induced Raynaud's phenomenon: beyond beta‐blockers

AIM Drug-induced Raynauds phenomenon (RP) has long been associated with the use of different drugs, including cancer chemotherapy or β-adrenoceptor blockers. However, sources report extremely variable prevalence and the level of evidence for each class is heterogeneous. Moreover, new signals are emerging from case reports and small series. Our objective was therefore to review available evidence about this adverse drug effect and to propose a mechanistic approach of drug-induced RP. METHODS A systematic review of English and French language articles was performed through Medline (1946-2015) and Embase (1974-2015). Further relevant papers were identified from the reference lists of retrieved articles. RESULTS We identified 12 classes of drugs responsible for RP, with a variety of underlying mechanisms such as increased sympathetic activation, endothelial dysfunction, neurotoxicity or decreased red blood cell deformability. Cisplatin and bleomycin were associated with the highest risk, followed by β-adrenoceptor blockers. Recent data suggest a possible involvement of tyrosine kinase inhibitors (TKI), through an unknown mechanism. CONCLUSION Drug-induced RP is a probably underestimated adverse drug event, with limited available evidence regarding its prevalence. Although rare, serious complications like critical digital ischaemia have been reported. When these treatments are started in patients with a history of RP, careful monitoring must be made and, if possible, alternative therapies that do not alter peripheral blood flow should be considered.

Foreseeable Advantages and Limits of Buprenorphine-Naloxone Association

Drug addiction is a chronic, relapsing disease that results from the prolonged effects of drugs on the brain. Opioid dependence is a worldwide problem. In opioid-dependent humans, buprenorphine is an effective treatment alternative to methadone (1,2) and levomethadyl acetate hydrochloride (3).The pharmacological profile of buprenorphine results in greater safety, less physical dependence, and greater flexibility in dose scheduling. However, abuse of buprenorphine has been reported in many countries where it is available as an analgesic (4) and in France (5), where it is available as an opiate-analgesic for drug substitution and maintenance. Despite the partial agonist activity of buprenorphine at µ opioid receptors and its “ceiling effect”, some cases of respiratory depression and fatalities have been reported, especially in cases of high doses of intravenously injected buprenorphine. The buprenorphine/naloxone (BupNx) combination tablet capitalizes on the differential absorption of naloxone by the sublingual (sl) vs parenteral routes: naloxone has a poor sl absorption. BupNx combination has been investigated with the goal of decreasing abuse, misuse, and diversion of buprenorphine. The BupNx combination product may be interesting for use in primary care office-based settings as a safe and an effective treatment that is likely to increase the availability of agonist treatment for opioid dependence. Availability of buprenorphine and BupNx tablets in United States has been slowed by the desire to provide them outside the traditional, highly regulated methadone clinic system. The Controlled Substances Act was amended in October 2000 and allows office-based prescribing of schedule III, IV, and V medications (and combination of medications) approved for opioid dependence and detoxification.