Insomnia (insomnia) is a widespread pathological condition, covering, according to published epidemiological data, 9-15% of the adult population of the world [1], and in Russia, according to survey results, its frequency can reach 20% [2]. Insomnia is characterized by recurrent problems with the initiation, duration, continuity or quality of sleep that occur in the absence of sufficient time and conditions for sleep and are accompanied by disruption of daytime activities. Short-term (lasting up to 3 months) insomnia disorders, which in the International Classification of Sleep Disorders (ICSD-3) [3] are classified as acute (short-term) insomnia, occur most often against the background of stressful situations and at certain periods of life and are observed in the majority of people. people [4]. The relevance of the problem of acute insomnia is due to the fact that in the presence of certain predisposing and perpetuating factors and in the absence of adequate treatment, it easily transforms into chronic, which is much less amenable to correction and causes a significant deterioration in health.
Among the drugs with a hypnotic effect used to treat insomnia, the H1-histamine receptor blockers diphenhydramine and doxylamine succinate (doxylamine) are widely known. Doxylamine, which appeared on the pharmaceutical market in 1948 [5], has a pronounced antihistamine, sedative and antiemetic effect (thanks to the latter, it is used in the complex treatment of nausea in pregnant women). A number of studies have demonstrated the positive effect of doxylamine drugs in the treatment of insomnia, comparable to the effect of benzodiazepines and so-called Z-hypnotics [6, 7]. Preparations in which the active ingredient is doxylamine (doxylamine preparations) are classified as over-the-counter sleeping pills in most countries. They do not cause dependence or withdrawal phenomena, and can be used for sleep apnea and during pregnancy, when most other sleeping pills are contraindicated. Restrictions on the use of doxylamine in the treatment of insomnia: anticholinergic effect of the drug, the possibility of developing side effects such as dry mouth, palpitations, constipation, urinary retention, headache, tremor, dizziness, impaired accommodation, drowsiness after waking up, etc. However, the side effects of the drug are rarely pronounced and therefore most often do not cause discontinuation of use. The main indication for the use of doxylamine is transient sleep disorders. In chronic insomnia, its use is not pathogenetically justified and may be accompanied by the formation of tolerance.
Until recently, the only doxylamine preparation on the pharmaceutical market of the Russian Federation was Donormil (Bristol-Myers Squibb, France). In 2013, the domestic drug doxylamine reslip (pharmaceutical enterprise Obolenskoye) was registered and included in the State Register of Medicines.
The purpose of this study is to evaluate the effectiveness of the drug Reslip in acute insomnia compared to the drug Donormil.
Material and methods
The multicenter open randomized study involved 6 medical FMBAs of Russia (Moscow), Irkutsk State Medical Academy of Postgraduate Education of the Ministry of Health of Russia (Irkutsk), a group of specialized medicine clinics "Medical Standard" (Ufa), and the Center for Aesthetic Medicine "Renovatsio" ( Krasnoyarsk), Federal State Budgetary Institution "Research Institute of Physiology and Fundamental Medicine" (Novosibirsk), Federal State Budgetary Educational Institution of Higher Education "Samara State Medical University" (Samara). The organizer and coordinator of the study was the all-Russian public professional organization “Russian Society of Somnologists”.
The study included 60 patients, including 35 (58.3%) women and 25 (41.7%) men, aged from 30 to 59 years, average age 43.7±1.04 years ( M±m
), suffering from transient sleep disorders with a frequency of 3 or more times a week lasting less than 3 months, who were first diagnosed with acute insomnia. Exclusion criteria: hypersensitivity to doxylamine or other components of the drugs and contraindications to their use (closed-angle glaucoma, prostatic hyperplasia, lactase deficiency, lactose intolerance, glucose-galactose malabsorption), diseases of internal organs in the stage of decompensation, an established diagnosis of obstructive sleep apnea syndrome or its high probability, the presence or high probability of other sleep disorders, severe cognitive impairment, alcoholism, drug or drug addiction.
Patients were randomized by serial number into two equal groups that did not differ in age and gender: group P (control) and group D (comparison) (Table 1).
Table 1. Sex and age composition of patient groups
Patients of group P ( n
=30) prescribed the drug Reslip at a dose of 15 mg orally 15-30 minutes before going to bed every day for 7-10 days.
Patients in group D ( n
=30) took the drug donormil in a similar dose and according to a similar schedule. Before treatment, the subjects of both groups filled out questionnaires to assess the severity of insomnia, subjective sleep quality and level of daytime sleepiness: Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Scale (PSQS) and Epworth Daytime Sleepiness Scale (EDS). After the end of therapy, the questionnaires were filled out again and the researcher assessed its clinical effectiveness (complete, partial, absence, deterioration) and the relationship with taking the drug. Side effects were assessed throughout the study. Data processing was carried out using statistical processing methods.
Reslip 15 mg, 10 film-coated tablets
Registration Certificate Holder
FP OBOLENSKOE (Russia)
Dosage form
Medicine - Reslip® (Reslip)
Description
Film-coated tablets
white or almost white, biconvex, oblong in shape with rounded ends, with a notch; On a cross section, the inner layer is white or almost white.
1 tab.
doxylamine succinate 15 mg
Excipients
: lactose monohydrate - 50 mg, colloidal silicon dioxide (Aerosil) - 0.5 mg, microcrystalline cellulose - 27.7 mg, croscarmellose sodium - 5 mg, povidone - 0.8 mg, magnesium stearate - 1 mg.
Film shell composition:
hypromellose (hydroxypropyl methylcellulose) - 1.8 mg, macrogol 6000 (polyethylene glycol 6000) - 0.6 mg, titanium dioxide - 0.6 mg.
10 pieces. — cellular contour packages (1) — cardboard packs. 10 pieces. — contour cell packaging (2) — cardboard packs. 10 pieces. — cellular contour packages (3) — cardboard packs. 10 pieces. — contour cell packaging (4) — cardboard packs. 14 pcs. — cellular contour packages (1) — cardboard packs. 14 pcs. — contour cell packaging (2) — cardboard packs. 14 pcs. — cellular contour packages (3) — cardboard packs. 14 pcs. — contour cell packaging (4) — cardboard packs. 28 pcs. — cellular contour packages (1) — cardboard packs. 28 pcs. — contour cell packaging (2) — cardboard packs. 28 pcs. — cellular contour packages (3) — cardboard packs. 28 pcs. — contour cell packaging (4) — cardboard packs. 30 pcs. — cellular contour packages (1) — cardboard packs. 30 pcs. — contour cell packaging (2) — cardboard packs. 30 pcs. — cellular contour packages (3) — cardboard packs. 30 pcs. — contour cell packaging (4) — cardboard packs.
Indications
- transient sleep disturbances.
Contraindications for use
- angle-closure glaucoma or family history of angle-closure glaucoma;
- diseases of the urethra and prostate gland, accompanied by impaired urine outflow;
- lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
- childhood and adolescence up to 15 years;
- hypersensitivity to doxylamine, other components of the drug or to other antihistamines.
Carefully:
patients with a history of apnea (due to the fact that doxylamine can aggravate sleep apnea syndrome); patients over 65 years of age (due to possible dizziness and delayed reactions with the risk of falls (for example, during night awakenings after taking sleeping pills), as well as due to a possible increase in T1/2); patients with renal and liver failure (T1/2 may increase).
pharmachologic effect
Histamine H1 receptor blocker from the ethanolamine group. It has a hypnotic, sedative and m-anticholinergic effect. Reduces the time to fall asleep, increases the duration and quality of sleep, does not change sleep phases.
Duration of action – 6-8 hours.
Drug interactions
With simultaneous use of the drug Reslip® with sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), barbiturates, benzodiazepines, clonidine, morphine derivatives (analgesics, antitussives), neuroleptics, anxiolytics, histamine H1 receptor blockers with a sedative effect, antihypertensive Centrally acting drugs, thalidomide, baclofen, pizotifen, enhance the inhibitory effect on the central nervous system.
When used simultaneously with m-anticholinergic drugs (atropine, imipramine antidepressants, antiparkinsonian drugs, atropine antispasmodics, disopyramide, phenothiazine antipsychotics), the risk of side effects such as urinary retention, constipation, and dry mouth increases.
Because ethanol enhances the sedative effect of most histamine H1 receptor antagonists, incl. drug Reslip®, it is necessary to avoid simultaneous use of this drug with alcoholic beverages and medications containing ethanol.
Dosage regimen
The drug is taken orally, 15-30 minutes before bedtime. Take the tablets with a small amount of liquid.
The recommended dose is 1/2-1 tablet/day. If treatment is ineffective, on the recommendation of a doctor, the dose can be increased to 2 tablets.
Duration of treatment - from 2 to 5 days; if insomnia persists, the patient should consult a doctor.
Due to data on increased plasma concentrations and decreased plasma clearance of doxylamine,
in patients with renal and hepatic insufficiency
.
Histamine H1 receptor blockers should be prescribed with caution to patients over 65 years of age
due to possible dizziness and slow reactions with the risk of falls (for example, during night awakenings after taking sleeping pills). In view of data on increased plasma concentrations, decreased plasma clearance and increased T1/2 of doxylamine, a dose reduction is recommended.
Overdose
Symptoms:
daytime drowsiness, agitation, mydriasis, accommodation disturbances, dry mouth, flushing of the skin of the face and neck, hyperthermia, sinus tachycardia, disorder of consciousness, hallucinations, decreased mood, anxiety, impaired coordination of movements, tremor, athetosis, convulsions (epileptic syndrome), coma .
Involuntary movements are sometimes a precursor to seizures, which may indicate severe poisoning. Even in the absence of seizures, severe doxylamine poisoning can cause rhabdomyolysis, which is often accompanied by acute renal failure. In such cases, standard therapy with constant monitoring of CPK activity is indicated.
If symptoms of poisoning appear, the patient should immediately consult a doctor.
Treatment:
symptomatic (m-cholinomimetics and other drugs), activated carbon is indicated as a first aid remedy (50 g for adults and 1 g/kg body weight for children).
Side effect
From the digestive system:
constipation, dry mouth.
From the cardiovascular system:
feeling of heartbeat.
From the side of the organ of vision:
visual impairment and accommodation, blurred vision.
From the nervous system:
drowsiness during the day (in this case, the dose of the drug should be reduced), confusion, hallucinations.
From the urinary system:
urinary retention.
From the laboratory parameters:
increase in CPK activity.
From the musculoskeletal system:
rhabdomyolysis.
If any of the adverse reactions indicated in the instructions worsen or any other adverse events not specified in the instructions are noted, the patient should inform the doctor.
special instructions
It should be taken into account that insomnia can be caused by a number of reasons for which there is no need to prescribe this drug.
The drug Reslip® has a sedative effect, suppresses cognitive abilities and slows down psychomotor reactions. The first generation of histamine H1 receptor blockers can have m-anticholinergic, anti-alpha-adrenergic and antiserotonin effects, which can cause dry mouth, constipation, urinary retention, disturbances of accommodation and vision.
Like all sleeping pills or sedatives, doxylamine may worsen sleep apnea by increasing the number and duration of sleep apnea episodes.
One tablet of the drug contains 50 mg of lactose monohydrate, which should be taken into account in patients with rare congenital galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption.
Impact on the ability to drive vehicles and operate machinery
Due to possible drowsiness during the daytime, you should avoid driving vehicles, working with machinery and other activities that require increased concentration and speed of psychomotor reactions.
Storage conditions
The drug should be stored out of the reach of children at a temperature not exceeding 25°C.
Best before date
Shelf life: 3 years. Do not use after the expiration date stated on the package.
Use during pregnancy and breastfeeding
Restrictions during pregnancy - No restrictions. Restrictions when breastfeeding - Contraindicated.
Based on adequate and well-controlled studies, doxylamine can be used in pregnant women throughout pregnancy.
If the drug is prescribed in late pregnancy, the atropine-like and sedative properties of doxylamine should be taken into account when monitoring the condition of the newborn.
It is not known whether doxylamine passes into breast milk. Due to the possibility of developing a sedative and stimulating effect in a child, breastfeeding should not be done while using the drug.
Use for renal impairment
Restrictions for impaired renal function - With caution.
The drug should be prescribed with caution to patients with renal failure.
Use for liver dysfunction
Restrictions for liver dysfunction - With caution.
The drug should be prescribed with caution to patients with liver failure.
Use in elderly patients
Restrictions for elderly patients - Use with caution.
The drug should be prescribed with caution to patients over 65 years of age.
Use in children
Restrictions for children - With caution.
The use of the drug is contraindicated in children and adolescents under 15 years of age.
Terms of sale
The drug is available with a prescription.
Contacts for inquiries
ALIUM JSC (Russia)
142279 Moscow region, Serpukhov working village Obolensk territory “Quarter A”, building 2 Tel./fax E-mail
results
Baseline assessments of insomnia severity, subjective sleep quality, and daytime sleepiness levels did not differ significantly between groups (Table 2).
Table 2. Initial assessments in groups on the ITI, PSHS and ESDS scales
According to the physician-researcher, in group P, 17 out of 30 (56.7%) patients achieved full clinical effectiveness in the treatment of acute insomnia, fully or partially associated with taking the drug, 12 (40%) achieved partial clinical effectiveness, 1 ( In 3.3%) cases, a lack of clinical effectiveness was observed. In group D, 18 out of 30 (60%) patients showed complete clinical effectiveness, fully or partially associated with taking the drug, 8 (26.7%) had partial clinical effectiveness, 2 (6.7%) had no clinical effectiveness , in 2 (6.7%) - worsening of acute insomnia. The differences between the groups turned out to be statistically insignificant.
After treatment in group P, the ITI index decreased to 8.5±0.89 points ( t
=9.55;
p
<0.001), PSHKS - up to 8.4±0.41 points (
t
=6.81;
p
<0.001), ESDS - up to 4.2±0.50 points (
t
=4.24;
p
<0.001) .
In group D, the ITI index decreased to 9.1 ± 0.97 points ( t
= 7.61;
p
< 0.001), PSHKS - to 8.8 ± 0.62 points (
t
= 5.27;
p
< 0.001), ESDS - up to 4.6±0.67 points (
t
=3.45;
p
<0.01). There were no statistically significant differences in post-treatment results between groups.
In group P, side effects were observed in 3 (10%) patients, including 2 - drowsiness in the morning after waking up, 1 - headache. In all cases, side effects were insignificant and did not cause discontinuation of the drug. In group D, side effects appeared in 7 (23.3%) patients: 2 - tremor, 1 - drowsiness in the morning after waking up, 1 - headache, 1 - mild dizziness, 1 - lack of appetite after waking up. In general (in 5 cases), side effects were insignificant and did not cause discontinuation of the drug. In 2 cases (tremor) the drug was discontinued. There were no significant differences in the frequency of side effects between the groups.
