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Comprehensive one-day renal function tests in 20 patients with a history of analgesic abuse showed varying degrees of chronic renal failure in all. There was no evidence of a selective defect in proximal tubular function, while a defective concentrating mechanism, usually considered necessary for the diagnosis of analgesic-induced renal damage, could be demonstrated in only 16 patients. A urinary acidification defect associated with a concentrating defect was found in nine cases and was thought to reflect specific collecting duct dysfunction. Urinary ammonium excretion was reduced in 13 subjects, owing to a reduced number of functioning nephrons or inadequate acidification, or both. Low citrate excretion was frequently encountered, and this, as well as defective urinary acidification, may play some part in predisposing patients with analgesic nephropathy to intrarenal calcification and progressive renal failure.

Radio-labeled dihydromorphine, morphine, methadone and levorphanol were administered to rats in pharmacologically active doses by the intracisternal route of administration, and the rats were killed 0.5 or 1 hr later. The drugs were localized in the fraction of brain containing the pinched-off presynaptic nerve-endings, the synaptosomes, as well as in the soluble portion of the tissue. The 14 C-labeled narcotic antagonists, naloxone and nalorphine, were also localized in the same particulate fraction of brain. The amount of drug in the synaptosomal fraction was dependent on the dose of drug, on the time between drug administration and sacrifice, and on the region of brain, and was specific for each narcotic agonist and antagonist. The relevance of this localization of narcotic analgesic drugs in the synaptosomal fractions of rat brain to the mechanism of action of the drugs remains to be explored.

A thin-layer chronmatographic procedure is described which is applicable to natural and synthetic alkoidal drugs. Neutral organic solvents are used to develop silica gel plates in an atmosphere of ammonia vapor. Identical results are given upon development of the plate when either the free base or a salt form is spotted for chromatography. The procedure is shown to offer more convenience and versality than an existing method in which alkaline silica gel layers are used.

In a retrospective study to compare the drug consumption during pregnancy of mothers of infants with congenital abnormalities and of those without, over 97% of 1,369 mothers took prescribed drugs and 65% self-administered drugs. Significantly more mothers of infants with congenital abnormalities took aspirin, antacids, dextroamphetamine, phenobarbitone, sodium amytal, other barbiturates, cough medicines, iron, sulphonamides, and nicotinamide than mothers in the control group. However, most mothers taking analgesics, antacids, appetite suppressants, barbiturates, cough medicines, iron, sulphonamides, and vitamins produced normal infants. Any teratogenic effect of these drugs is therefore one of low potency. On the other hand, deficiencies such as those of ascorbic acid and folic acid may have a teratogenic effect. There is need for caution in presuming teratogenic effects on the basis of the associations shown here. During pregnancy, however, it would appear wise to avoid the administration of any drug which carries a suspicion of teratogenicity unless that drug is specifically indicated, and self-medication with common household remedies such as aspirin and antacids should be avoided. These recommendations would also apply to any woman of childbearing age in whom conception is likely.

Pain may be attacked in the rheumatic diseases (1) centrally, with drugs ranging in efficiency from those which are potentially addictive and under the Dangerous Drugs Act (e.g., pethidine) and are therefore rarely used, down to simple analgesics such as paracetamol; (2) peripherally, by local action, whether it be by applications of heat or cold, by injections of local anaesthetics or anti-inflammatory agents, or by surgery; (3) peripherally, by anti-inflammatory non-analgesic agents taken systemically, such as the corticosteroids; and (4) peripherally, by anti-inflammatory-analgesic-antipyretic agents taken systemically, such as aspirin.The exact sites of action of the pyrazoles, indomethacin, the anthranilic compounds, and other anti-inflammatory-analgesic-antipyretic drugs are as yet uncertain, but along with these methods of attacking the pain-producing areas help must also be given to the distressed mind behind the joints. Faith in the future, cheerfulness, freedom from depression, and the development of a philosophy to deal with the uncertainties of the disease are essential. It has been said that you don't have to be a doctor to treat uncomplicated lobar pneumonia: anybody with a bottle of penicillin in his hands holds the cure. It is the incurable diseases that are really worth treating, and that make demands on the physician. To quote Tuker: "My last word is this. Whoever has the care of a sorely stricken arthritic must encourage him to fulfil himself intellectually and spiritually, and to achieve-no matter what, but to achieve, so that he may nightly lay himself down on his bed of pain looking forward happily to the morrow's task, mind centred upon it, no matter what it is; sticking in stamps, research into anything you like, dabbling with pastel or water colours, writing chatty letters to friends. Anything at all, but let it be for him the most pressing thing of the day, and let him believe that you think it is. Help him and let him live, live fully."This is perhaps the best analgesic of all.

Of 14 patients with analgesic nephropathy 11 were followed up for 9 to 88 (mean 36) months after withdrawal of analgesics containing phenacetin. Ten of these 11 are still alive and have improving, static, or very slowly declining renal function. Analgesic withdrawal is therefore worth achieving even in the presence of advanced renal failure. Careful prolonged follow-up is required to prevent or detect relapse and to deal with the complications of prolonged renal failure, particularly bone disease and acidosis. Early diagnosis is life-saving in this condition. Attention is drawn to the diagnostic value of sterile pyuria, but the best screening test for the condition is careful interrogation of all patients with chronic renal disease of unknown aetiology; analgesic intake is rarely denied if asked for specifically.

A double-blind cross-over study of ketoprofen (Orudis) 150 mg daily and ibuprofen (Brufen) 1,200 mg daily was carried out in 35 outpatients with rheumatoid arthritis. Results suggest that analgesic and anti-inflammatory activity of ketoprofen is superior to that of ibuprofen. Significantly greater pain relief (P < 0·05) and reduction in joint circumference (P < 0·01) was obtained with ketoprofen than with ibuprofen. Side effects of the drugs were comparable and not serious.

Pain threshold was measured in 106 patients with rheumatoid arthritis, 50 with ankylosing spondylitis, and 50 normal controls using Keele's algometer. In rheumatoid arthritis patients with a low pain threshold had more severe pain for a greater part of the day and required more tablets for pain relief. In ankylosing spondylitis the pain threshold was higher and was not related to pain or analgesic requirements. There was no evidence that pain threshold affected the course or outcome of rheumatoid arthritis in any way.

Benorylate (4-acetamidophenyl 2-acetoxybenzoate) is a new esterified aspirin preparation whose antirheumatic properties are reported to be as good as those of aspirin. Gastrointestinal blood loss, measured with (51)Cr-labelled red cells, during benorylate therapy was compared with that during therapy with soluble aspirin in 15 subjects, a simplified crossover procedure being used. Mean blood loss during benorylate therapy was 1.7 ml/day which was significantly less than that during therapy with soluble aspirin (5.1 ml/day; P

A series of experiments has been carried out with single doses of simple analgesics in patients with rheumatoid arthritis using a consistent polyad design. This method proved to be both valid and useful. Pain relief scores were a better measure of the effectiveness of analgesics than preference. Aspirin, Codis, and Distalgesic were the most effective analgesics tested, with paracetamol, pentazocine, and Ciba 44,328 intermediate between these agents and placebo. Placebo given after an active analgesic was more effective than when given before; this phenomenon was not abolished by telling the patients that apparently identical tablets were, in fact, different or by making them different in colour. The effectiveness of soluble placebo depended on its colour, red being the most effective.

Three patients developed a vasculitis while taking alclofenac. Two recovered with corticosteroid therapy, and the third, who had continued to take the drug for a further week despite epistaxis, haemoptysis, haematuria, and cutaneous vasculitis, developed a more persistent vasculitis with histological evidence of progressive renal involvement.

Eight out of ten of patients with analgesic nephropathy were regular and usually heavy laxative takers compared with 12 out of 200 controls from the general population and four out of 70 patients attending a renal clinic. The finding that regular laxative taking was greatly increased in patients with analgesic nephropathy suggests that this condition may often be due to the combined abuse of both laxatives and analgesics. In a series of 40 patients with rheumatoid arthritis all were found to have normal renal function and no patient took laxatives regularly. This finding would explain why analgesic nephropathy is so uncommon in patients with rheumatoid arthritis despite the fact that they are regular and heavy analgesic takers.

Challenge tests with some analgesics in common use were performed in five aspirin-sensitive asthmatics. Marked falls in FEV(1) were observed after ingestion of paracetamol, indomethacin, mefenamic acid, and dextropropoxyphene in some subjects. The mechanisms of analgesic-induced asthma are discussed: it is believed to be a non-immunological process of great practical importance when prescribing analgesics to asthmatics.

2,3,6-Triaminopyridine (TAP), a metabolite of pyridium (DPP), is an unstable substance which decomposes readily in aqueous solution to yield colored oxidation products. No evidence was obtained that TAP was metabolized by direct ring hydroxylation, either in vivo (rabbit) or in vitro (rabbit-liver enzymes). The results indicated rather that the 2-amino group in the TAP molecule was replaced by a hydroxyl group during metabolism.A maximum of 15% of the administered dose of TAP was excreted unchanged, and from 1 to 25% was recovered as metabolites that could be acetylated by acetic anhydride to 2,3,6-triacetamidopyridine (TACP).The intraperitoneal LD50 of TAP was found to be 76 mg/kg in mice, which is considerably less than that of its parent compound DPP. The increased toxicity of TAP may de due to TAP itself, its colored oxidation products, or a metabolite.

Thirteen analgesic drugs, four of them at two dose levels, four analgesics in combination with antagonist or neuroleptic agents, and saline have been evaluated simultaneously in the relief of postoperative pain. The method of assessment was designed to favour drugs which provided freedom from pain with minimum depression of consciousness. Only levorphanol 2 mg proved significantly superior to pethidine 100 mg, which was used as the standard reference drug. Oxycodone 10 mg, pentazocine 20 mg, and the morphine 10 mg and cyclizine 50 mg combination were the most successful of the remaining drugs. None of the drug combinations was significantly better than the analgesic drug given alone.

In a double-blind between-patient study of aspirin and benorylate carried out in 72 outpatients with rheumatoid arthritis, benorylate 4 g twice daily was shown to be an effective analgesic and anti-inflammatory drug, its effects being indistinguishable from those of aspirin 1·2 g four times daily. Compared with the pretreatment values both drugs produced a statistically significant improvement (P < 0·01) in functional grade, overall pain, articular index, and grip strength at the end of the first and second weeks. The overall incidence of side effects was less with benorylate, though this difference was not significant at the 5% level.

SummaryMP-2001, a lower poly alkoxy derivative of estradiol, exhibits analgesic activity in a variety of animal species, including man. MP-2001 does not possess estro-genic activity. It is rapidly excreted from the body without radical change of the basic ste-roidal nucleus.

Radioactive narcotic analgesics, including morphine, dihydromorphine, nalorphine, codeine, levorphan, dextrorphan, and l -methorphan were accumulated against an apparent concentration gradient in pieces of rabbit and dog choroid plexus and in slices of dog renal cortex by a metabolically dependent mechanism. The uptake of dihydromorphine by these tissues in vitro was a saturable process depressed by low temperatures, a nitrogen atmosphere, and certain metabolic inhibitors. It also was competitively inhibited by nalorphine and by any one of several organic bases which previously have been demonstrated to be actively transported by these tissues. Under certain conditions, stimulation of dihydromorphine uptake by choroid plexus was produced by organic bases. The transport in choroid plexus of one of these organic bases, hexamethonium, was competitively inhibited by dihydromorphine. Studies with levorphan and dextrophan indicated an element of stereospecificity in their accumulation by choroid plexus. Thus it is concluded that the narcotic analgesics share the same active transport mechanisms described for a variety of organic bases that are accumulated in choroid plexus and renal tissue in vitro . Suggestions are made relative to the significance of these observations for the intact animal.

Narcotic analgesics have been shown to be accumulated in cerebral cortical slices by a process having the characteristics of an active transport system. In addition, diffusion and binding contributed to the total uptake of the analgesics into brain slices. The total uptake of dihydromorphine (1 × 10 −6 M in medium) was found to reach steady state equilibrium in 30 min at 37° with a maximum tissue to medium concentration ratio ( T M ) of 2.3. Accumulation in vitro of the narcotic analgesics in brain differed from their accumulation in the kidney and in the choroid plexus in that there was a lower ( T M ) ratio at equilibrium for brain and the uptake by brain was not inhibited by quaternary organic bases. The narcotic analgesic antagonist, nalorphine, consistently depressed the uptake of dihydromorphine in a competitive manner.