Drugs for dysmenorrhea.

PIP: Primary dysmenorrhea may be due to excessive prostaglandin synthesis; therefore, drugs which inhibit prostaglandin production may be of value in treating dsymenorrhea. The effectiveness of various analgesics and antiarthritic protaglandin inhibiting drugs in treating dysmenorrhea is reviewed. Several clinical trials indicate that ibuprofen and mefenamic acid are more effective in reducing mild and moderate dysmenorrhea than aspirin. Side effects associated with ibuprofen use included gastrointestional and visual disturbances, and those associated with mefenamic acid were gastrointestional and hematological toxicity. Some anti-inflammatory drugs used to treat arthritis also inhibit prostaglandin production and have been evaluated in terms of their effectiveness in treating dysmenorrhea. Clinical trials of indomethacin and naproxen indicate these drugs to provide relief from dysmenorrhea. A number of negative side effects are associated with prolonged use of indomethacin. Naproxen is not currently available in the United States. Some physicians have found that administering prostaglandin drugs prior to the onset of menstruation enhances their effectiveness. Other physicians advise against this practice and administer the drugs only after menstruation begins in order to rule out the possibility of pregnancy. The effect of these drugs on the fetus is unknown. Larger clinical trials and studies of the long term effects of using these drugs are needed.^ieng

Flufenamic acid in treatment of primary spasmodic dysmenorrhoea. A double-blind crossover study.

A double-blind cross-over trial of flufenamic acid three times a day (200 mg) was carried out in forty-four patients with primary dysmenorrhoea. While on flufenamic for 3 months 82% of patients experienced significant pain relief. Associated gastrointestinal symptoms, i.e--vomiting and diarrhoea--were relieved in 66% and 52% patients respectively while on flufenamic acid. It is concluded that the fenamates are useful and safe drugs in the treatment of primary dysmenorrhoea.

PIP: The efficacy of flufenamic acid (3 times/day in 200 mg doses) was tested in a double-blind crossover study, using 44 primary dysmenorrheic patients. After 3 months of use, flufenamic relieved symptoms in most patients. Associated gastrointestinal symptoms were relieved in 66% and 52% (for vomiting and diarrhea, respectively), and 28% of patients experienced cessation of pain symptoms. 4 cases of drug-induced side effects were reported: dizziness and mild dyspepsia.

Potential therapeutic agents derived from the cannabinoid nucleus.

PIP: Drugs derived from Cannabis sativa (Cannabinceae) were used until the 1940's for their stimulant and depressant effects for treating somatic and psychiatric illnesses. Renewed interest in marihuana research began in the 1970's and again pointed to the therapeutic potential of cannabinoids. Safer and more useful therapeutic agents may be generated from cannabinoids similarly to morphine, lysergic acid diethylamide, and cocaine which have structurally related analgesics, oxytoxics, and local anesthetics respectively. It has been shown that the C-ring in cannabinoids can be substituted with a variety of nitrogen and sulfur-containing rings without loss of CNS (central nervous system) activity. Cannabinoids have been shown to inhibit prostaglandin synthesis, intensify pressor effects of endogenous amines like norepinephrine, and enhance the stimulant effects of amphetamine. Cannabinoids' therapeutic potential lies in the areas of analgesics and anticonvulsants, and for use as a sedative-hypnotic, an antiglaucoma agent, an antiasthmatic agent, an antidiarrheal agent, and possibly as an anticancer and immunosuppressant agent.^ieng

Trial of prostaglandin-synthetase inhibitors in primary dysmenorrhoea.

The prostaglandin-synthetase inhibitors, mefenamic acid and flufenamic acid, were compared with the analgesic, dextropropoxyphene/paracetamol, in the treatment of primary dysmenorrhoea in a double-blind crossover trial. Results were assessed in 30 patients who took each drug during menstruation for three consecutive cycles. The patients' assessment of each drug suggests that both mefenamic acid and flufenamic acid are more effective than the other analgesic for general relief of symptoms and for most of nine individual symptoms subjectively assessed by the patient. There was less absenteeism from work or school during mefenamic-acid treatment and fewer capsules of mefenamic acid were taken compared with the other two drugs. Patients took significantly fewer additional analgesics during mefenamic-acid therapy than during treatment with the other two drugs. 5 patients had possible side-effects--3 patients on mefenamic acid and 2 on dextropropoxyphene/paracetamol.

PIP: In a double-blind corss-over trial, 30 patients experiencing primary dysmenorrhea were treated with 2 prostaglandin inhibitors, mefenamic acid (250mg) and flufenamic acid (100 mg), and an analgesia, dexhropropoxyphene (32.5 mg)/paracetamol (325 mg) (D.H. and P.). The patients took each drug for 3 consecutive cycles and were subjectively assessed. Results indicate that there was no significant difference between mefenamic acid and flufenamic acid nor flufenamic acid and D.H. and P.; however, mefenamic acid was significantly better than D.H. and P. The total number of mefenamic acid capsules taken was significantly less than either flufenamic acid or D.H. and P. In rating side effects, mefenamic acid was significantly better in reducing the effects of faintness, nausea, and constipation and flufenamic acid was statistically significant in reducing nausea. There were possible side effects in 3 women taking mefenamic acid and in 2 women taking D.H. and P.

The effect of ibuprofen on the intrauterine pressure and menstrual pain of dysmenorrheic patients.

In 12 dysmenorrheic patients we examined the therapeutic action of the Prostaglandin-synthesis inhibitor: Ibuprofen, a non-steroidal analgesic agent. Ibuprofen highly significantly reduced the resting pressure (P less than 0.001), active pressure (P less than 0.001) and frequency (P less than 0.05) of cyclic activity of the uterus, as well as menstrual pain (P less than 0.001). Since these effects occurred after a single oral dose of 800 mg Ibuprofen, without side effects or complications, extensive field trials are recommended with this and other PG-synthesis inhibitors, to assess their therapeutic benefits.

PIP: 12 dysmenorrheic volunteers (average age, 28 years) were studied after treatment with Ibuprofen, a nonsteroidal antiinflammatory agent. Intrauterine pressure was recorded after either placebo or Ibuprofen oral administration. 800-mg doses were used. The therapeutic action of this prostaglandin inhibitor was highly significant in reducing resting pressure (P.001), active pressure (P.001), and frequency of contractions (P.05). In addition, menstrual pain was significantly reduced (P.05). The success of this single dose of 800 mg makes feasible a more comprehensive clinical trial of Ibuprofen's therapeutic effects.

The refief of primary dysmenorrhea by ketoprofen and indomethacin.

The prostaglandin biosynthesis inhibitors ketoprofen and indomethacin were compared in the treatment of primary dysmenorrhea in a double-blind, cross-over trial involving 23 patients. Each drug was used for 2-4 days during 3 consecutive menstruations in randomized order. Good or moderate overall relief was obtained in 60 of the 68 ketoprofen-treated menstruations (88%). A dysmenorrhea score, based on subjective estimations of 8 symptoms, similarly decreased from a mean (+/- S.E.M.) basal level of 9.6 +/- 0.6 to 3.6 +/- 0.3 during ketoprofen treatment and to 4.0 +/- 0.3 during indomethacin. Both drugs relieved pelvic and lower back pains and eliminated vomiting and diarrhea in 82-97% of the cycles whereas headache, fatigue and nervousness were less frequently alleviated (40-67%). Eighteen of the 23 women (78%) had been unable to work during the first day of menstruation, the rate of working days lost was reduced to 4% with ketoprofen and 9 with indomethacin. Mild side-effects occurred during 12 ketoprofen and 14 indomethacin therapies. Ketoprofen thus seems to be as effective and tolerable as indomethacin in the treatment of primary dysmenorrhea.

PIP: Ketoprofen and indomethacin were compared as specific therapies for primary dysmenorrhea in this study involving 23 primary dysmenorrheic women; the study was double-blind and cross-over. Each patient was given a code-numbered package of capsules of ketoprofen (50 mg) or indomethacin (25 mg); medication (1 capsule 3 times daily) was started 1 day before menstruation and was continued until cessation of dysmenorrheic symptoms (no longer than 4 days). Patient estimation of the effect of ketoprofen was ranked as good in 70% of cases, moderate in 18%, and nil in 12%. For indomethacin, the figures were 58, 31, and 10%, respectively. Initial dysmenorrhea score of 9.6 was reduced to 3.6 during ketoprofen therapy and to 4 with indomethacin (P.001). Ketoprofen alleviated pelvic pain in 84% of cases; indomethacin in 78%. Mean duration of pelvic pain was reduced to 5.1 hours from an initial period of 10.6 hours with ketoprofen and 5 hours with indomethacin (P.01); this statistic excluded cycles of total relief. Other symptoms relieved were similar with both drugs, including: lower back pain, vomiting, diarrhea, and dizziness (alleviated in 82-97%) and headache, fatigue, and nervousness (alleviated in 40-67%). Blood loss was subjectively estimated to decrease in 42% and increase in 4% of ketoprofen-treated patients, whereas for indomethacin these figures were 36% and 7%, respectively. All side effects were mild. The rate of lost working days was significantly decreased under both treatments.

Anaprox in dysmenorrhea: reduction of pain and intrauterine pressure.

In a double-blind parallel trial, 24 dysmenorrheic women received a single dose of Anaprox (1,100 mg) or placebo. Over the next 2 hours, pain intensity was scored and intrauterine pressure was measured using an immobilized microballoon. At the end of 2 hours, all 11 patients given Anaprox (but only three of the 13 given placebo) experienced complete pain relief (p = 0.0004). The resting intrauterine pressure (IUP) decreased from a mean of 51.4 to 26.8 mm Hg in the Anaprox-treated group, while in the placebo group the mean resting IUP values remained essentially unchanged ( drop from 55.4 to 51.9 mm Hg was observed). This difference between the two treatment groups was statistically significant in favor of Anaprox (p = 0.03). Several patients from each group were given 0.2 mg of ergonovine by intramuscular injection following the 2 hour trial. In both groups, the resting IUP increased within 30 minutes; the corresponding increase in pain intensity was more pronounced, however, in the placebo group. These results support the premise that a decrease in resting IUP is directly linked to the pain-relieving effects of Anaprox.

PIP: 24 women with regular menstrual cycles but suffering from dysmenorrhea were studied in a double-blind parallel trial to determine the effects of anaprox on pain reduction. 11 patients received anaprox (1100 mg) and 13 received placebos while a microballoon-tipped catheter was inserted into the uterine cavity to measure intrauterine pressure. After 2 hours, all patients experienced complete pain relief and their IUP (intrauterine pressure) decreased from a mean 51.4 to 26.8 mm Hg, while only 3 of the 13 patients experienced relief having a mean IUP decrease from 55.4 to 51.9 mm Hg. Patients who showed the greatest reduction in IUP also showed the most pain relief. 6 of the 11 women were given ergonovine by injection and although their IUP increased their dysmenorrhea was minimal; whereas, in 7 of the 13 women given ergonovine injection, 4 had an increase in dysmenorrhea within 30 minutes.

Prostaglandin biosynthesis inhibitors and endometriosis.

Prostaglandins (PGs) may be involved in the development of the symptoms of endometriosis. Therefore 18 patients with pelvic endometriosis were treated in placebo controlled double-blind trial with different prostaglandin biosynthesis inhibitors. These drugs were: acetylsalicylic acid (0.5 g x 3) exerting a weak PG-synthetase inhibition, indomethacin (25 mg x 3) inhibiting PG-synthetase, and as a representative of fenamates, tolfenamic acid (200 mg x 3), which both inhibits PG-synthetase and antagonizes PGs at the target level. The therapeutic effect was evaluated using a specific endometriosis score separately during menstruation and in premenstrum. Prostaglandin biosynthesis inhibitors did not alleviate premenstrual complaints better than placebo. During menstruation tolfenamic acid relieved endometriotic symptoms more effectively than placebo while indomethacin and acetylsalicylic acid did not differ from placebo. A drug which inhibit both the synthesis and action of PGs can thus be used in the alleviation of secondary dysmenorrhea due to endometriosis.

PIP: The possible role of prostaglandins (PGs) in the biochemistry of endometriosis prompted this placebo-controlled double-blind trial evaluating the effect of PG-inhibitors on symptoms of endometriosis (especially pelvic pain). The 4 drugs used were: 1) placebo, 2) acetylsalicylic acid (ASA), 3) indomethacin, and 4) tolfenamic acid. Each drug was administered orally from Day 20 of the menstrual cycle until end of menstruation for 2 consecutive cycles. During menstruation, tolfenamic acid (P.01) and ASA (P.05) lowered the endometriosis score from the pretreatment level. Tolfenamic acid was more effective than placebo (P.05), whereas ASA and indomethacin did not differ from placebo. Each treatment, including placebo, lowered the endometriosis score (P.05) during the menstrual period, but none of the PG inhibitors was more effective than placebo (P.05). According to patient's subjective judgements, tolfenamic acid alleviated symptoms more effectively than other drugs tested. Pain symptoms occurred less often during tolfenamic acid and ASA than during placebo or indomethacin (P.05). Gastrointestinal side effects were more common with indomethacin and ASA (P.05). Indomethacin treatment raised the incidence of psychic complaints over those with ASA or placebo (P.05). Side effects were fairly evenly distributed among the therapies.