MEMORANDUM
From: Kirsten Myhr, MscPharm, MPH, Member Expert Advisory Panel on Drug Policies and Management
To: Co-ordinator, WHO EDL Committee meeting April 2002
Date: 6 April 2002
Subject: Revision of the essential drugs list
I have in a separate letter commented on the classification system, more specifically the use of the ATC classification system and inclusion of the DDDs.
The Committee in the 1999 edition comments that certain sections are in urgent need of review (pages 46-52, sections 14.2, 15, 17.1, 17.6, 17.7, 22, 27). In addition, I assume that the list will change now or later anyway as a result of what will be recommended in the new WHO Formulary, the revised guidelines on hypertension and other evidence-based guidelines. Comments on inclusions and deletions may therefore be of limited value and I have not put a lot of effort into proposals for reviewing the current list. No systematic survey or evaluation of literature has been done.
In the two-page document called "Essential Drugs - Suggestions for Review", WHO lists a group of miscellaneous items, asking whether they should be on the list at all. Some are not what would be classified as medicines, but others are. In my opinion and in accordance with the current (Norwegian) definition of medicines (substances, herbals and preparations intended for or used in the prevention, treatment or alleviation of human or animal illness, or pain, or for internal or external use in the diagnosis of illness), diagnostics are medicines and they should therefore be kept. Others on the current list are more doubtful, such as topical preparations for sun protection and insect repellents. Not mentioned are technical disinfectants and nicotine for stopping smoking (mentioned in the comments page 50 on psychotherapeutic drugs) which in my opinion are more unlikely items on the list. It might be that if all these items are kept, and if some of the suggestions for this meeting are approved, the list should actually change name.
1. Anaesthetics
Chloral hydrate
In the ED-list it is included as a preoperative tranquillizer for children and it is powerful as such (Dollery. Therapeutic drugs 2nd ed.). According to the listing by Richard Laing and colleagues of 12 national lists to see how many have recommended substances from the WHO list, it is on only two national lists. In spite of the, not so well documented, preoperative use in children, I am therefore in doubt whether it should retain its place on the list.
This is what is said in the Micromedex (vol. 112, exp. 06/2002) evaluation under "place in therapy": "Chloral hydrate may be used preoperatively or pre-procedurally to allay anxiety or produce sedation. Chloral hydrate is often used in children because many clinicians believe it produces less paradoxical excitement than the barbiturates; however, no well-controlled studies have confirmed this."
And these are the review articles listed:
1. Pharmacologic options for sedation in children before procedures have been reviewed (Bhatt-Mehta & Rosen, 1998). Specific procedure guidelines for pediatric sedation in nuclear medicine have been published (Mandell et al, 1997).
2. The Committee on Drugs & Committee on Environmental Health (1992 to 1993) of the American Academy of Pediatrics published their report on the Use of Chloral Hydrate for Sedation in Children in Pediatrics Vol 92, No 3, September 1993.
On the topic of sedation of children, see also e.g. the Scottish Guidelines: Safe sedation of children undergoing diagnostic and therapeutic procedures (
Oral solutions of chloral hydrate needs to be diluted in large amounts of water. I have previously proposed that rectal administration might be a better choice if the substance is to be kept on the list.
Ephedrine
I think dr Offerhaus' comments are valid for the uses he mentions, but as I understand the list, it is included as injection as a complementary drug in anaesthesia. However, even for that use its value may be limited. According to the above mentioned review of national lists, it is on none of the 12 national essential drugs lists.
2. Analgesics etc.
Codeine
I agree with dr Offerhaus that it is a problematic drug and when included in combination products, often is found in a subtherapeutic dose. There are, however, few alternatives. E.g. tramadol, is also addictive, has several side effects and interaction potential and is more costly. It has also been included in the list for treatment of diarrhoea and cough.
Pethidine (meperidine)
In chronic pain management, the general consensus at present is that pethidine has no role to play. (see e.g. Molloy A. Does pethidine still have a place in therapy? Austr Prescriber 2002; 25(1): 12-3). Its metabolites are pharmacologically active, one being potentially seizure inducing and because of its long half-life may accumulate even when renal function is normal. Pethidine also has more cardiovascular effects than morphine and may therefore have a larger interaction potential.
Even in labour its role may be questionable, particularly when other methods are available (epidural). "Pethidine has mainly a sedative effect, but very little analgesic effect in parturients. Pethidine has relatively long-acting behavioural and neurological effects in the newborn due to slow elimination. As a result, breastfeeding is delayed and the mother-infant interaction is disturbed according to recent studies. There is concern about the more or less routine administration of pethidine in many hospitals. We conclude that obstetric departments should reconsider their use of pethidine". (Matheson I, Nylander G. Should pethidine still be administered to women in labour? Tidsskr Nor Laegeforen 1999; 119: 234-6).
A Cochrane review: Types of intra-muscular opioids for maternal pain relief in labour concludes: There is not enough evidence to evaluate the comparative efficacy and safety of the various opioids used for analgesia in labour.
In my opinion there is no need to keep both morphine and pethidine on the list. An alternative mentioned for treating severe pain is ketorolac (Jelinek GA. Ed. Ketorolac versus morphine for severe pain. Ketorolac is more effective, cheaper, and has fewer side effects. BMJ 2000;321:1236-7)
5. Anticonvulsants
Clonazepam
Clonazepam is recommended by some for treatment of epilepsy because of its longer duration of action than diazepam. However, it is now widely misused because of its capacity to induce tolerance and dependence. Although it may still have a place as an alternative treatment in some of the myoclonic epilepsies of childhood (2), its inclusion on the list should be reviewed.
References:
1. Feely M. Drug treatment of epilepsy. BMJ 1999; 318: 106-9.
2. Panayiotopoulos CP. Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs 2001: 3(5): 379-403.
Micromedex (vol. 112, exp. 06/2002) says on its place in therapy: "Clonazepam has been useful in treating absence seizures in patients refractory to conventional therapy. Clonazepam has also been effective in controlling sensory-precipitated epilepsy such as photomyoclonic or "reading" epilepsy. Partial complex seizures and focal seizures do not respond as well to clonazepam as to other drugs. Although clonazepam may be as effective as diazepam in treating status epilepticus, the drug's usefulness is limited by its cardiorespiratory depressant effects."
8. Antineoplastic drugs
I agree with dr Offerhaus that this group has grown out of proportion and its size and content bears no relation to other groups on the list. As dr Offerhaus says, most of the drugs are to be used in highly specialised units. A drug like chlormethine has highly any indication in cancer therapy any more and is a problematic drug also from the point of toxicity and physical and chemical properties. The Committee mentions that the evidence for deleting asparaginase, chlormethine, dacarbazine and levamisole was unclear and they were therefore kept. This is to some extent understandable for asparaginase which is frequently used in relapses of leukaemia in children, but less so for the others. It should also be mentioned, when there is such concern for including other new substances on the list because of cost, that many of the substances in this group are very expensive.
Calcium folinate
I do not know whether calcium folinate (leucovorin) has been put here for its role as adjunct to fluorouracil in the treatment of advanced colorectal cancer, but if it is not, it must be as antidot to methotrexate and should be moved to group 4.
The listing of fluorouracil cream (under dermatologicals) does not seem justified. It is only found on two out of the 12 national lists reviewed.
12. Cardiovascular drugs
Methyldopa
According to the above mentioned review of national lists, it is on 10 out of 12 such lists.
I think it is difficult to give advice here. I think for routine HT its risk/safety profile does not warrant routine use, but for HT in pregnancy it seems to be still the drug of choice, if that condition is at all to be treated, see Cochrane reviews below. The WHO guidelines on hypertension are under revision and will probably give recommendations even for pregnancies? I have looked at the Cochrane database which has two relevant reviews:
1. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Conclusion: It remains unclear whether antihypertensive drug therapy for mild-moderate hypertension during pregnancy is worthwhile.
2. Oral beta-blockers for mild to moderate hypertension during pregnancy.
Conclusion: The improvement in control of maternal blood pressure with use of beta-blockers would be worthwhile only if it were reflected in other more substantive benefits for the mother and/or baby, and none have yet been clearly demonstrated. The effect of beta-blockers on perinatal outcome is uncertain, given that the worrying trend to an increase in small for gestational age infants is partly dependent on one small outlying trial.
Large, randomised controlled trials are needed to determine whether antihypertensive therapy in general (rather than beta-blocker therapy specifically) results in benefits that outweigh the risks for treatment of mild-moderate pregnancy hypertension. If so, then it would be appropriate to look at which antihypertensive is best. Beta-blockers would remain a candidate class of agents.
There is also a recent Cohcrane review supporting the use of calcium supplementation in women at high risk of gestational hypertension and in communities with low calcium intake.
The Micromedex (vol 112, exp 06/2002) evaluation says:
"Methyldopa is safe and effective for use during pregnancy and is one of the most extensively used agents to treat hypertension in these patients. In others, because of frequent side effects, it is a reserve agent.
Methyldopa warrants formulary inclusion for the treatment of hypertensive pasients who are pregnant or resistant to treatment with first-line agents."
Procainamide and quinidine
The list has procainamide for injection and quinidine for oral use. Digoxin and lidocaine are alternatives. Although Micromedex mentions that procainamide might be better tolerated for iv use than quinidine, but less for longterm use, it should be discusssed whether there is a need for both, if for any.
Micromedex (vol. 112, exp 06/2002) on place in therapy for both:
A. Procainamide is an effective Class IA antiarrhythmic agent, with activity against both ventricular and supraventricular arrhythmias. The Medical Letter consultants consider procainamide to be an alternative to digoxin for long-term suppression of atrial arrhythmias (Anon, 1989). Other alternatives include quinidine and disopyramide. Because of the high incidence of increased ANA titers and lupus-like syndrome with long-term use of procainamide, quinidine is generally preferred for chronic therapy (Woosley & Funck-Brentano, 1988). When intravenous therapy is required, procainamide is felt to be better tolerated than quinidine (Woosley & Funck-Brentano, 1988; Young & Koda-Kimble, 1988).
B. Procainamide is considered an alternative to lidocaine for the treatment of ventricular tachycardia, ventricular fibrillation, or tachyarrhythmias induced by digitalis (Anon, 1989).
C. Antiarrhythmic drugs have not been shown to improve survival in patients with ventricular arrhythmias. In addition, use of class I antiarrhythmic drugs (e.g. procainamide) has increased the risk of death when used in patients with non-life-threatening arrhythmias (Anon, 1995).
A. Quinidine is an effective class IA antiarrhythmic agent with broad-spectrum activity against ventricular, supraventricular and atrial arrhythmias. Quinidine minimally depresses left ventricular function; however, it has been associated with pro-arrhythmic complications, which in some cases have been fatal. Therefore, this agent should be administered to carefully selected patients (ie, patients with intermittent atrial fibrillation, sustained ventricular tachycardia) and used with caution (Salerno, 1992; AMA, 1992).
B. Use of quinidine and other antiarrhythmic drugs have not been shown to improve survival in patients with ventricular arrhythmias. In addition, use of class I antiarrhythmic drugs (eg, quinidine) has increased the risk of death when used in patients with non-life-threatening arrhythmias (Anon, 1995).
C. Quinidine is generally preferred over procainamide for long-term treatment of arrhythmias due to the more frequent occurrence of increased ANA titers and lupus with procainamide (AMA, 1992). However, when intravenous therapy is needed, many clinicians feel that procainamide is generally better tolerated than quinidine (Young & Koda-Kimble, 1988; Woosley & Funck-Brentano, 1989).
Reserpine
I think there is documentation to support keeping it as a low cost alternative. Here are five relevant references from Medline, note in particular that it is included in the guidelines in South Africa, even after a recent revision of the guidelines.
1. Kronig B, Pittrow DB, Kirch W, Welzel D, Weidinger G.Different concepts in first-line treatment of essential hypertension. Comparison of a low-dose reserpine-thiazide combination with nitrendipine monotherapy. German Reserpine in Hypertension Study Group. Hypertension. 1997 Feb; 29(2): 651-8.
2. Griebenow R, Pittrow DB, Weidinger G, Mueller E, Mutschler E, Welzel D.Low-dose reserpine/thiazide combination in first-line treatment of hypertension: efficacy and safety compared to an ACE inhibitor. Blood Press. 1997 Sep; 6(5): 299-306.
3. Manyemba J. A randomised crossover comparison of reserpine and sustained-release nifedipine in hypertension. Cent Afr J Med. 1997 Dec;43(12): 344-9.
4. Seedat YK.Hypertension in developing nations in sub-Saharan Africa. J Hum Hypertens. 2000 Oct-Nov;14(10-11): 739-47. Review.
5. Hypertension clinical guideline 2000. S Afr Med J. 2001 Feb; 91(2 Pt 2):163-72.
6. Fraser HS.Reserpine: a tragic victim of myths, marketing, and fashionable prescribing.
Clin Pharmacol Ther. 1996 Oct; 60(4): 368-73.
Micromedex recommends it to be considered for formulary inclusion as a supplementary drug for hypertension.
13. Dermatological drugs
Methylrosanilin
I agree with the Committee that at present the risks does not outweigh the benefits and it should be kept on the list
Sodium thiosulfate
It is difficult to find justification for keeping sodium thiosulfate as an antifungal. It is on only one out of the 12 national lists reviewed.
(Technical) disinfectants should be moved as they have nothing to do with use on the skin.
17. Gastrointestinal drugs
In line with the policy of using single drug products, antacids are listed as either aluminium salts or magnesium salts. In my opinion this is a drug class where there is a rationale for using combination products, because the combination may reduce side effect as magnesium tends to give diarrhoea and aluminium constipation. The combination, which is the most frequently used preparation in developed countries, should reduce the frequency of side effects. It is only in patients with reduced kidney function that there is a need to avoid aluminium.
It has now been proposed to delete aluminium hydroxide, I propose again to substitute both of them with a combination product.
A more physiologic working laxative such as lactulose or a magnesium salt should be added.
18. Hormone disorders and contraception
Nonoxylenol
I agree with dr Offerhaus that it should be deleted. JAMA of 6 March 2002 carries an article and an editorial justifying that:
Roddy RE, Zekeng L, Ryan KA, Tamoufé U, Tweedy KG. Effect of nonoxynol-9 gel on urogenital gonorrhea and chlamydial infection. JAMA 2002; 287(9): 1117-22.
Richardson BA. (Ed) Nonoxynol-9 as a vaginal microbicide for prevention of sexually transmitted infections. It's time to move on. Editorial. JAMA 2002; 287(9): 1171-2.
22. Oxytocics
Salbutamol (albuterol)
The Cochrane database has two reviews:
1. Tocolysis for preventing fetal distress in second stage of labour:
Conclusion: There is no evidence to support the prophylactic use of betamimetics during the second stage of labour.
2. Tocolytics for suspected intrapartum fetal distress:
Conclusion: Betamimetic therapy appears to be able to reduce the number of fetal heart rate abnormalities and perhaps reduce intrauterine activity. However, there is not enough evidence based on clinically important outcomes to evaluate the use of betamimetics for suspected fetal distress.
Dollery (Therapeutic Drugs 2nd ed.): "Albuterol, like other selective beta2-stimulants, has an inhibitory effect on the myometrium, producing a demonstrable decrease or abolition of uterine contractions in advanced labour in a dose-dependant manner. Its efficacy in prolongation of labour beyond 37 weeks' gestatation has, however, been doubted ….. This type of treatment is contraindicated after antepartum haemorrhage or in the presence of toxaemia of pregnancy. Caution is necessary in the presence of cardiac disease. Should not be used in the management of threatened abortion."
This all supports a proposal for revising its inclusion.
25. Drugs acting on the respiratory tract
Aminophylline and theophylline
Here I agree with the comments made by dr Offerhaus. Looking at a couple of recent guidelines (UK, Canada) I could only find aminophylline as a last choice for management of acute severe asthma in hospitals. On oral theophylline the British guidelines says on alternative treatments: "may be useful in some patients but should be used with care in view of potential side effects and drug interactions". ( The Canadian guidelines says: "In a few patients, there may be a role for bronchodilators such as theophylline and ipratropium."
(
Dextrometorphan
For a review of the evidence of OTC drugs for cough, reference is made to the following article:
Schroeder K, Fahey T. Systematic review of randomised controlled trials of over the counter cough medicines for acute cough in adults. BMJ 2002; 342: 1-6.
26. Solutions correcting water, electrolyte ….
26.2. I think there should be a sodium chloride additive 1 or 2 mmol/ml (or 1.5 as for potassium)
27. Vitamins and minerals
The list does not contain all vitamins, but the ones that are listed appear as single items.
Whether this is because of the policy of not recommending combination products or because vitamins are only recommended to be used in deficiency states attributable to specific vitamins, I cannot say. I think however, it causes a waste of money and irrational use. In most cases, except may be for vitamins A and D and occasionally for C, the remaining vitamins are then being used not in deficiency states, but whenever people self-diagnose themselves, by symptoms, to have a disease caused by a deficiency in e.g. vitamin B1 or B6.