LEADING ARTICLE

Clin. Pharmacokinet. 23 (4): 249-252. 1992 0312-5963/ 92/0010-0249/$02.00/0 © Adis International Limited. All rights reserved. CPK1218

Insulin Pens Is Delivery Sacrificed to Improve Patient Compliance? Derek Gordon Law Hospital. Near Carluke. Lanarkshire, England

The diagnosis of insulin-dependent diabetes mellitus necessitates an immediate and lifelong alteration in the lifestyle of the diabetic patient. Diabetes requires a fundamental modification of the patient's diet with the introduction of dietary restrictions and the need for careful timing of meals and snacks. Patients must learn to match the amount of exercise they undertake to their insulin requirements. Patients also face a future of daily self-injection with insulin. While this may be the most daunting and unpleasant aspect to their diagnosis it is the one aspect of their management which cannot be ignored. Compliance with insulin therapy is therefore high except in a few cases (mainly teenagers) when self-denial of their diagnosis can result in a rejection of all advice regarding treatment. Nevertheless, if insulin therapy can be made more convenient and acceptable then this will surely enhance the quality of life of the diabetic patient. It was to this end that the first insulin pen device was developed (Paton et al. 1981). Although insulin was discovered and first administered 70 years ago (Banting et al. 1922) the goal of physiological delivery remains elusive. The subcutaneous route of administration does not mimic the natural secretion of the pancreatic islet cells into the portal venous system. Approximately half the insulin released into the portal system is removed by the liver during its first passage (Polonsky & Rubenstein 1984). The liver is therefore exposed to concentrations of insulin which are twice those present in the general circulation. Insulin has

profound effects on liver glycolysis and gluconeogenesis and this concentration gradient may be of physiological importance. When insulin is administered by the subcutaneous route this concentration difference between the systemic and portal venous systems cannot be realised. In healthy humans, insulin is secreted by the pancreas at a basal rate of about I U Ih. Following a meal there is a rapid 5- to 10-fold rise in insulin secretion rate and plasma levels reach a sharp peak before declining promptly to basal levels. Exercise similarly results in rapid changes in insulin secretion. Such rapid alterations in plasma insulin level cannot be simulated by the slow absorption from the subcutaneous site. Table I. Advantages and disadvantages in the use of insulin pens

Advantages

Disadvantages

They allow acceptability of multiple insulin injection regimens

Multiple insulin injection regimens may allow excessive weight gain without improved metabolic control (Gordon et al. 1992)

Multiple insulin injection regimens improve patient lifestyle Increased accuracy and reliability of insulin delivery Pens can be used by those with impaired vision or coordination

Inaccuracy of malfunctioning pens may go unrecognised by patients The elderly may find them too complex to use

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In an attempt to more closely mimic the physiological secretion of insulin, basal-bolus regimens for insulin delivery were introduced. Such schemes involve the administration of bolus injections of soluble insulin before meals, along with either continuous subcutaneous infusion of insulin or the use of a single daily injection of long-acting (lente) insulin. The development of insulin pen devices allowed the introduction of such multiple insulin injection regimens to take place with a high degree of acceptability (Berger et al. 1985; Houtzagers & van der Velde 1988; Jefferson et al. 1985; Jensen et al. 1986; Murray et al. 1988; Walters et al. 1985) [table I]. There is no doubt that in highly motivated patients who monitor blood glucose levels frequently (at least 5 times daily) and alter insulin doses according to algorithms, tight metabolic control can be achieved (Schiffrin & Belmonte 1982). Subsequent studies in large clinic populations have, however, failed to identify improvement in overall metabolic control using such intensified treatment regimens (Gordon et al. 1992). Multiple insulin injection therapy does not improve diabetic control. Its value, however, lies in its ability to improve patients' lifestyle by freeing diabetic individuals from the restrictions of regimented meal times and closely proportioned carbohydrate intake. The limitations of subcutaneous insulin administration have been demonstrated in many studies. Analysis of the peak plasma insulin levels and the area under the dose-response curve after repeated injections in a single patient at the same anatomical site and with the same dose and technique shows a coefficient of variation of 20 to 30% for both soluble (regular) and intermediate acting insulins (Galloway et al. 1986). The peak effect and duration of action also increase with increasing insulin dosage. To complicate matters still further, insulin absorption varies according to the injection site. Soluble insulin injected into the abdominal wall is absorbed 86% faster than from the leg and 30% faster than from the arm (Koivisto & Felig 1980). Absorption of isophane insulin does not appear to be influenced to the same extent by injection site (Henriksen et al. 1991). The subcutaneous

Clin. Pharmacokinet. 23 (4) 1992

adipose tissue of the thigh appears to be the preferred site of injection of isophane insulins since the rate of absorption is most constant from this area. The presence of lipohypertrophy at injection sites also influences rates of insulin absorption. Exercising the limbs will increase the rate of absorption as do other determinants of cutaneous circulation such as environmental temperature (Berger et al. 1979; Zinman et al. 1977). Recently, attention has been turned to the technique of insulin injection, since evidence has suggested that conventional advice regarding injection technique may result in the delivery of insulin intramuscularly rather than to the subcutaneous tissues (Thow & Home 1990). Thus, the depth of insulin injections will also affect absorption kinetics. An additional problem can be the accuracy of measuring a required insulin dose. Kesson and Bailie (1981) measured the accuracy of insulin doses drawn up by both trained nurses and diabetic patients. Nurses were shown to measure insulin doses with an error of 4.4% and reproducibility of 3.15%. Diabetic patients less than 40 years of age showed marginally less precision while diabetics aged over 40 years were even less accurate. This latter group showed an error in dose measurements of 19.3% and a dose reproducibility of 7.1 %. Puxty and colleagues (1983) showed that even when older diabetic patients (mean age 66 years) with impairments in vision, cognition and coordination were excluded from such studies, the inaccuracy of administration was still significant, at 12.2%. How then do pen devices compare with conventional needles and syringes for accuracy of insulin delivery? There is little doubt that they are much more accurate than the average syringe user. The manufacturers of the original NovoPen (Novo Industry, Copenhagen Denmark) claimed a dosage error of less than 2% (personal communication). Similarly the manufacturers of the Humulin Cartridge (Eli Lilly, Basingstoke, UK) and B-D Pen (Becton Dickinson, Cowley, UK) claim an average dose accuracy of 99.8% and 99.1 % of the target dose for the 4-unit and 26-unit dose levels, respectively. Furthermore, they claim no significant deteriora-

Insulin Pens

tion in this accuracy after 5 years of simulated use (personal communication). Bench-testing of pen devices, however, fails to simulate the normal wear and tear of pens used in the community. We have shown that the accuracy of NovoPen I devices deteriorates after 3 years of patient use and that in a small number of devices (less than 4% of pens tested) the error in dosage can be as high as 83.5% with a reproducibility of only 23.5%. It is not surprising that patients using these pen devices had shown a previously unexplained deterioration in metabolic control (Gordon et al. 1990). The commonest cause for this gradual deterioration in pen accuracy was dirt in the pen mechanism. It is likely that all mechanical devices for insulin delivery will be susceptible to deteriorating precision if misused or roughly handled. Patients must therefore be encouraged to have a healthy scepticism towards their insulin pens. If unexpected deterioration in metabolic control occurs in a patient using an insulin pen, the pen device should come under suspicion. Manufacturers should be encouraged to provide simple methods and protocols which would allow patients to assess the precision of their pen devices. While the meticulous care required for the sterilisation of the old glass syringes is no longer required, patients should be encouraged to keep their pens free of dust and sand. There is no doubt that the convenience of insulin pens will ensure their continuing popularity. Their value for the accurate metering of insulin to the older diabetic, particularly those with impaired vision or coordination, has probably been understated and never confirmed in practice. It should be emphasised, however, that the accuracy of insulin dosage and administration is but a single variable in the total delivery of insulin via the subcutaneous or intramuscular route. The use of pen devices has allowed the widespread acceptance of multiple insulin injection regimens which, in turn, have freed the patient with diabetes from some dietary restrictions and allowed a more flexible lifestyle. There is no evidence that insulin pens compromise drug delivery. Indeed, as long as they are not

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mishandled and are recognised to have a finite working lifetime, they should deliver insulin accurately and reliably.

References Banting FG, Best CH, Collip JB, Campbell WR, Retcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Canadian Medical Association Journal 12: 141-146, 1922 Berger AS, Saurbrey N, Kuhl C, Villumsen J. Oinical experience with a new device that will simplify insulin injections. Diabetes Care 8: 73-76, 1985 Berger M, Halban PA, Assai JP, Offord RE, Vranic M, et al. Pharmacokinetics of subcutaneously injected tritiated insulin: effects of exercise. Diabetes 28: 53-57, 1979 Galloway JA, Spradlin cr, Howey DC, Dupre J. Intrasubject differences in pharmacokinetic and pharmacodynamic responses: the immutable problem of present-day treatment? Proceedings of the 12th Congress of the International Diabetes Federation, Madrid, September 23-28, 1985, International conference Series No 700, Exerpta medica, Amsterdam, pp. 877-886, 1986 Gordon D, Wilson M, Paterson KR, Semple CG. An assessment of the accuracy of Novo Pen delivery after prolonged usage. Diabetic Medicine 7: 364-366, 1990 Gordon D, Wilson M, Paterson KR, Semple CG. An audit of multiple injection regimens in a large outpatient diabetic population. Diabetes Research and Clinical Practice, in press, 1992 Henriksen JE, Vaag A, Ramsgaard Hansen I, Lauritzen H, Djurhuus MS, et al. Absorption of NPH (lsophane) insulin in resting diabetic patients: evidence for subcutaneous injection in the thigh as the preferred site. Diabetic Medicine 8: 453-457, 1991 Houtzagers CMGJ, van der Velde EA. Multiple daily injections: a multicentre study on acceptability and efficacy. Netherlands Journal of Medicine 33: 16-25, 1988 Jefferson IG, Marteau TM, Smith MA, Baum JO. A multiple injection regimen using an insulin injection pen and prefilled cartridged soluble human insulin in adolescents with diabetes. Diabetic Medicine 2: 493-497, 1985 Jensen T, Moller L, Ortved Andersen O. Metabolic control and patient acceptability of multiple insulin injections using NovoPen cartridge-packed insulin. Practical Diabetes 3: 302-306, 1986 Kesson CM, Bailie GR. Do diabetic patients inject accurate doses of insulin? Diabetes Care 4: 333, 1981 Koivisto VA, Felig P. Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients. Annals of Internal Medicine 92: 59-61, 1980 Murray DP, Keenan P, Gayer E, Salmon P, Tomkin GH, et al. A randomized trial of the efficacy and acceptability of a pen injector. Diabetic Medicine 5: 750-754, 1988 Paton JS, Wilson M, Ireland JT, Reith SBM. A convenient pocket insulin syringe. Lancet I: 189-190, 1981 Polonsky KS, Rubenstein AH. C-peptide as a measure of the secretion and hepatic extraction of insulin: pitfalls and limitations. Diabetes 33: 486-494, 1984 Puxty JAH, Hunter DH, Burr WA. Accuracy of insulin in-

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jection in elderly patients. British Medical Journal 287: 1762, 1983 Schiffrin A, Belmonte M. Multiple daily self-glucose monitoring: its essential role in long-term glucose control in insulin-dependent diabetic patients treated with pump and multiple subcutaneous injections. Diabetes Care 5: 479484, 1982 Thow J, Home P. Insulin injection technique: depth of injection is important. British Medical Journal 301 : 3-4, 1990 Walters DP, Smith PA, Marteau TM, Brimblet A, Borthwick U . Experience with NovoPen, an injection device using

cartridged insulin, for diabetic patients. Diabetic Medicine 2: 496-497, 1985 Zinman B, Murray FT, Vran ic M, Albisser AM, Leibel BS, et al. Glucoregulation during moderate exercise in insulin treated diabetes. Journal of Clinical Endocrinology and Metabolism 45: 641-652, 1977

Correspondence and reprints: Dr D. Gordon. Consultant Physician, Law Hospital, Carluke, Lanarkshire ML8SER, England.

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Insulin pens. Is delivery sacrificed to improve patient compliance?

LEADING ARTICLE Clin. Pharmacokinet. 23 (4): 249-252. 1992 0312-5963/ 92/0010-0249/$02.00/0 © Adis International Limited. All rights reserved. CPK121...
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