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The Original Article on intravenous magnesium sulphate in neuropathic pain caught Strollers eye last year (Crosby V., Wilcock A. and Corcoran R. The Safety and Efficacy of a Single Dose (500mg or 1g) of Intravenous Magnesium Sulphate in Neuropathic Pain Poorly Responsive to Strong Opioid Analgesics in Patients with Cancer. J Pain and Symptom Manage 2000; 19: 35-38). It is known that magnesium acts as an NMDA antagonist and has also been shown to improve migraine and post-operative pain when given intravenously. An earlier paper documented improvement in chronic neuropathic pain of varying aetiologies following a bolus and infusion of intravenous magnesium chloride. This particular article documents 12 patients with either brachial or lumbo-sacral plexus neuropathy, the first half of whom were given a single injection (IV) of 500mg magnesium sulphate over 5 minutes, with good tolerance, and subsequently the second six patients were given 1000mg over 10 minutes. Patients had been excluded if they had hypermagnesaemia, hypercalcaemia, uraemia > 12 mmol/l, heart block or were taking digoxin. All patients experienced a sensation of warmth for 2-3 minutes only, usually over the upper chest or in the perineum, more marked with the larger dose. There were no significant or symptomatic changes in heart rate or blood pressure. After the 1000mg dose, serum magnesium levels increased transiently by a mean of 0.3 mmol/L from baseline measurements of 0.7-0.9mmol/L settling to normal within an hour toxic levels said to be above 2.0 mmol/L. As far as efficacy is concerned, overall four patients experienced complete relief of pain (three from 500mg dose) and a further six partial relief, maximal after 45-60 minutes and extending up to 4 hours. 2 patients had no benefit, one from each dose group. This small research project is interesting although many questions remain unanswered. Further larger studies are awaited eagerly to validate the suggested benefits and to determine dosing (size, route, frequency) including maintenance therapy.

Stroller has previously felt the need to remark on some of the hazards of uncontrolled Chinese herbal medication. The Committee on Safety of Medicines and Medicines Control Agency have become wary of such products and report on hypoglycaemia following use of Xiaoke Wan, which was found to contact glibenclamide (Hypoglycaemia following use of Chinese herbal medicine Xiaoke Wan. MCA/CSM Current Problems in Pharmaco-vigilance. February 2001; 27: 8). Sold from traditional Chinese Medicine outlets, only the product name and manufacturer, Kwangchow First Chinese Medicine Factory, Guangzhou, Peoples Republic of China, are in English. Container labelling and the leaflet, when provided, is in Mandarin. This alert followed hypoglycaemic coma after ingestion.

In contrast to the above, St. Johns Wort (Hypericum perforatum) has become popular, particularly as a treatment for mild depression, and, as a naturally occurring plant remedy used for centuries, has been thought to be harmless natural therapy. Crude plant extracts however, contain a number of pharmacologically active compounds with central nervous system activity.

This includes inhibition of the uptake of serotonin, noradrenaline and dopamine, stimulation of GABA receptors and weak monoamine oxidase inhibition. The most commonly reported adverse reactions are gastro-intestinal symptoms, allergic reactions, dizziness, confusion, tiredness/sedation and dry mouth, most being mild-moderate and transient. Over and above these effects, another edition of Current Problems in Pharmacovigilance (CSM/MCA Reminder: St. Johns Wort (Hypericum perforatum) interactions. Current Problems in Pharmacovigilance May 2000; 26:6), reminds us of drug interactions due to the induction of various drug-metabolising enzymes, including cytochrome P450, and also of the transport protein, P-glycoprotein. Problems are further increased by variations in levels of active ingredients from one preparation of St. Johns Wort to another. The following drugs could be reduced in efficacy: Warfarin, carbamazepine, phenytoin, phenobarbitone, digoxin, theophylline, cyclosporin, oral contraceptives, HIV protease inhibitors and HIV non-nucleoside reverse transcriptase inhibitors. In contrast, triptans for migraine and SSRIs for depression will give rise to increased serotonergic effects and adverse reactions.

Bandolier is a good source of guidance for evidence-based practice in neat digestible quantities. A recent article, Things that affect our INR (Bandolier 2001 May;8(5):5-6), highlighted a case control study from Massachusetts General Hospital, Boston where 93 out of 2000 patients, anti-coagulated with Warfarin, were found to have an INR of >6.0 (6.1-30) over a single year. (Hylek E.M. et al. Acetaminophen and other risk factors for excessive Warfarin anti-coagulation. JAMA 1998; 279: 657-662 and Bell W.R. Acetaminophen and Warfarin. Undesirable synergy. JAMA 1998; 279: 702-703). These 93 and matched controls, with INR maintained 1.7-3.3 (target 2.0-3.0), were interviewed regarding relevant habits over the 4 weeks prior to the abnormal or control tests. Information was gathered about medicines (new, old and over-the-counter), dietary change specifically including 12 foods with high vitamin K content (avocado, broccoli, sprouts, cabbage, peas, lettuce, liver, spinach etc), alcohol consumption, and prescribed and consumed warfarin dosage. Independent risk factors for an increased risk of INR > 6.0 were in order of significance: advanced malignancy, newly commenced medicines with potential to interact, consumption of more warfarin than prescribed, a decreased ingestion of foods rich in vitamin K and acute diarrhoeal illness. Conversely, eating more vitamin K rich foods and a moderate alcohol intake (one drink on alternate days to two drinks daily) were associated with a lower risk of increased INR. Paracetamol (acetaminophen) had a notable effect on increasing the INR. More than nine 500mg tablets weekly gave an odds ratio of 7, and more than eighteen tablets an odds ratio of 10, in elevating INR to greater than 6.0. We now need to consider adding Paracetamol-based analgesia to aspirin and NSAIDS amongst contra-indicated medications with Warfarin. Perhaps we also need to review our use of Warfarin in patients with advanced malignancy, considering both the risks/benefits of any anti-coagulation and the substitution of low molecular weight heparins?

q Radiation-induced mucosal toxicity is most commonly seen in patients undergoing radiotherapy to the head and neck, oesophagus and pelvis. Pain, nausea and vomiting, and diarrhoea are the most common symptoms of side-efects and significantly hinder quality of life. Various medications have been used to diminish aggravation of toxicity and to induce mucosal healing. A selection of these had been discussed at the Annual Meeting of the Swedish Society for Oncology in 1997 (Henriksson R. et al – Aspects on Reducing Gastrointestinal Advise Effects Associated with Radiotherapy. Acta Oncologica 1999;38:159-164). The agents discussed in this article were sucralfate, amifostine and camomile as protection against mucositis, and 5HT3 antagonists for prevention of emesis following abdominal radiotherapy. Sucralfate, safe, cheap and simple to use, has been found to be particularly effective in reducing abdominal side-effects following pelvic radiotherapy and is thought to exert a local protective effect on the gut mucosa- by forming a viscous protective barrier on the mucosal surface. It is also postulated that sucralfate may also be cytoprotective at a biochemical level. Amifostine is an interesting compound originally developed in the U.S.A. during a major research project which analysed over 4000 potential radio-protectors to protect troops exposed to irradiation from nuclear warfare. Compound 2721, amifostine, was least toxic and most effective but, as far as the Army were concerned, interest waned as the drug needed to be ingested prior to radiation exposure. Hence, its further application to therapeutic irradiation, where it is thought to work cytoprotectively by a combination of free-radical scavenging, hydrogen atom donation to facilitate direct chemical repair at sites of DNA damage, and induction of anti-oxidation processes to produce intracellular hypoxia. Amifostine is concentrated in normal tissues, where alkaline phosphatase is much higher than in tumour and breaks down the drug to an active metabolite. It also possesses anti-mutagenic properties. Few clinical studies have yet been done perhaps mainly because pre-clinical studies have also suggested a tumour-protective effect, possibly with a requirement for a higher effective dose of irradiation and therefore the risk of further toxicity. Camomile has many medicinal properties such as anti-pyretic, anti-bacterial, anti-mucotic, anti-flogistic, spasmolytic, and calming and sedative effects. Several of these actions could be helpful in reducing mucositis. A German preparation of the probably active lipophilic components of camomile (Kamillosan??-Astra Pharmaceuticals) has been used in some trials with differing results. Further randomised studies are needed for yet another long-used herbal preparation! Ondanestron has been shown to reduce vomiting 2-3 weeks following fractionated abdominal radiotherapy in randomised controlled trials, and also to reduce diarrhoea. The anti-emetic effect would appear to be superior to other anti-emetics.

q Stroller recently looked back over some articles outlining studies and experience with opioids given by continuous subcutaneous infusion all of which appeared in the Journal of Pain and Symptom Management. Taken chronologically, a retrospective study of fentanyl was published which concluded the usefulness of subcutaneous infusion in patients with previously uncontrolled pain on a fentanyl patch (for 3 out of 5 patients) and in patients with toxicity on other opioids (morphine, hydromorphone) of whom 10 out of 17 achieved analgesia with improvement in toxicity in 7. (Watanabe S, Bruera E. et al – Fentanyl by Continuous Subcutaneous Infusion for the Management of Cancer Pain:A Retrospective Study. J Pain Symptom Manage 1998;16:323-326). The median conversion ratio for morphine prior to change to stable fentanyl levels was 85.4 (range 65-112.5) and for hydromorphone to fentanyl was 23.0 (range 10.7-29.7). The suggested starting point of titration after changing from morphine to fentanyl was 100:1. Equianalgesic dosing was suggested for transfer from transdermal to subcutaneous routes. Subcutaneous hydromorphone, available in the Republic of Ireland, was compared to subcutaneous morphine in a double-blind randomised, controlled trial, published in 1999 (Miller M et al – Continuous Subcutaneous Infusion of Morphine vs. Hydromorphone: A Controlled Trial. J Pain Symptom Manage 1999;18:9-16). The study was conducted in patients who were terminally ill, of whom 28% died prior to completion of the 72 hour study period and of whom 85% were unable to complete the simple assessment card themselves. The conversion ratio of subcutaneous morphine: hydromorphone used was 5:1 and results suggested that this ratio resulted in inadequate doses of hydromorphone in 48% of this group. However, 35% of the morphine group also required an increase in dose after 24 hours rendering uncertainty to any comments about the conversion ratio inferred as inadequate by the previous statement. In this study, both drugs were well-tolerated. Subcutaneous methadone has also been trialled (Mathew P, Story P – Subcutaneous Methadone in Terminally Ill Patients:Manageable Local Toxicity. J Pain Symptom Manage 1999;18:49-52 and Makin M. – Letter:Subcutaneous Methadone in terminally ill patients. J Pain Symptom Manage 2000;9:237-238). The main messages from these communications relate to local toxicity of subcutaneously infused methadone. The former article describes reduced inflammation at the infusion site with addition of 1-2 mg Dexamethasone/24 hours to the methadone infusion thus increasing the duration of an individual infusion site from a mean of 2.6 days to 4.9 days. The latter favours the addition of hyaluronidase 1500 IU to the infusion in the larger volume of 20 mls. and routinely changing the site daily. These are certainly different styles to achieve a similar objective. Stroller would favour the hyaluronidase in view of the drug incompatibilities brought about by the presence of dexamethasone in the infusion and precluding the concomitant use of other drugs including glycopyrrolate, cyclizine and methotrimeprazine. Dose conversion is only touched upon with the suggestion that subcutaneous methadone is twice as potent as the oral drug. Further comment on conversion ratios between morphine and methadone has been made by other authors including Bruera and De Conno and their teams over the last five years. The conversion ratio depends on complicated and poorly understood factors and conversion therefore requires careful titration, which can be achieved in different ways. A recent review summarises the information gathered from the literature on opioid dose ratios (Anderson R. et al – Accuracy in Equianalgesic Dosing: Conversion Dilemas. J Pain Sympton Manage 2001:2:397-406).