Br. J. clin. Pharmac. (1978), 6, 75-79
COMPLIANCE WITH ANTICONVULSANT THERAPY IN A HOSPITAL CLINIC AND IN THE COMMUNITY J.C. MUCKLOW & C.T. DOLLERY Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W1 2 OHS 1 Seizure control, saliva anticonvulsant concentration, prescribing habits and compliance with anticonvulsant medication have been compared in 86 epileptic subjects attending either a specialist hospital clinic or general practice surgeries. 2 Of all subjects experiencing recurrent seizures 7096 had saliva concentrations of phenytoin below the range equivalent to the 'therapeutic range' of plasma concentration. Mean saliva phenytoin concentrations did not differ significantly between the two treatment settings and were low largely because of the low mean dosage prescribed. 3 Eleven subjects in all had no detectable phenytoin in their saliva and could clearly be identified as noncompliant. Freedom from seizures appeared to predispose to poor compliance in these subjects as well as among those admitting repeated omission of doses.
Introduction
Methods
Seizure control amongst epileptic subjects receiving anticonvulsant therapy is known to be influenced by the treatment setting and this is partly due to differences in patient compliance. Kutt, Haynes & McDowell (1966) found that unreliable drug intake was responsible for apparent refractoriness to phenytoin therapy in twelve out of sixteen out-patients studied. Gibberd, Dunne, Handley & Hazleman (1970) reported significantly lower plasma concentrations of phenytoin among out-patient epileptics than among in-patients. Supervision of drug taking in both these studies led to increased plasma phenytoin and improved seizure control. Plasma concentration of phenytoin is a wellestablished guide to drug dosage in epileptic subjects and correlates well with control of seizures (Buchthal, Svensmark & Schiller, 1960) but the need for venepuncture limits the wide use of this measurement. Saliva phenytoin concentrations provide a reliable index of concentration in plasma (Bochner, Hooper, Sutherland, Eadie & Tyrer, 1974) and this is also true of phenobarbitone (Cook, Amerson, Poole, Lesser & O'Tuama, 1975). The majority of epileptics do not attend hospital clinics on a regular basis and their anticonvulsant therapy is supervised by a general practitioner. Our stjdy was designed to compare seizure control, saliva phenytoin concentration, prescribing habits and compliance with medication in the context of hospital out-patient clinic and general practice surgery.
The study involved 86 epileptic patients, 50 of whom attended a Neurology Clinic at Hammersmith Hospital and 36 whose anticonvulsant therapy was supervised by general practitioners in the North Hammersmith District (these two groups will be referred to as the Hospital Group and the General Practice Group). The overall sample age range was 12-75 years. There were equal numbers of males and females in the Hospital Group while the General Practice Group comprised 21 males to 15 females. All patients were receiving phenytoin sodium (as capsules or sugar-coated tablets) and the majority were having one or more additional anticonvulsant drugs. Treatment had in every case been instituted at least 3 months prior to involvement in this study. Each patient's drug regime was recorded precisely by the doctor on a questionnaire. The name of each drug, tablet size, number of tablets per day and timing of each dose were recorded. The number of seizures experienced during the preceding 3 months was also entered. Carefully-worded questions were then asked by the doctor about compliance with therapy (see Figure 1). The exact timing of the last dose of phenytoin was recorded. All patients were weighed. At least 3 ml of mixed saliva were collected from each patient after allowing a single 25 mg tablet of ascorbic acid to dissolve in the mouth. Tongue and cheek movements provided a further stimulus for salivary flow. The sample, in a 'Sterilin' plastic container, was stored frozen. After thawing, the saliva was centrifuged for 10 min at 1800 rev/min and the' concentrations of phenytoin and phenobarbitone in
.* Present address: Department of Pharmacological Sciences, University of Newcastle-upon-Tyne, NE1 7RU
76
J.C. MUCKLOW & C.T. DOLLERY
How often do you forget to take a dose of phenytoin
majority (67%) were receiving phenytoin and phenobarbitone either separately or in combined preparations. In neither group was seizure control significantly better amongst patients taking more than one anticonvulsant drug. All patients were taking their drugs in at least two divided doses each day. If all drugs (anticonvulsant and others) were considered, 64% of the Hospital Group and 80.6% of the General Practice Group were taking three or more doses each day and more than half of all patients were taking six or more tablets each day. The mean daily doses (in mg/kg) of phenytoin, phenobarbitone and primidone did not differ significantly between the two groups (Table 3).
or phenobarbitone?
Never Occasionally Once or twice a week Every other day Every day At what time of day are you most likely to forget?
Morning Midday Evening Bedtime Other
Omission of doses (Table 4)
Nature of questions asked about Figure 1 compliance.
the supernatant were measured, using the gas chromatographic method of MacGee (1976) as modified by Vajda, Williams, Davidson, Falconer & Breckenridge (1974). Statistical analyses were performed using Student's unpaired t-test and chi-squared test.
Results
The mean age was 32 years in the Hospital Group and 37.6 years in the General Practice Group. Of the Hospital Group 52% and of the General Practice Group 64% had been free from seizures during the 3 months preceding the study (Table 1).
Anticonvulsant therapy
Therapeutic regimens varied considerably in the Hospital Group (Table 2) and only 36% were receiving phenytoin alone. The remainder were also taking phenobarbitone and/or primidone. A small number were also receiving other drugs such as carbamazepine, sodium valproate, acetazolamide and ethosuximide. In the General Practice Group the Table I Number of patients having seizures in preceding 3 months
Hospital Seizures No seizures Total
group
General Practice group
24 26 50
13 23 36
54% of patients in the Hospital Group and 50% in the General Practice Group admitted omitting doses at least occasionally. However, only five patients admitted to missing a dose more than once or twice a week. Although the midday dose was the one most commonly omitted, a substantial number in each group confessed to forgetting either the morning or the evening dose from time to time. In no patient did the occurrence of side effects appear to contribute to poor compliance. In the Hospital Group there was a significantly greater (P< 0.01) incidence of seizures (16 out of 23) amongst those patients who denied omitting doses at any time than amongst those who confessed periodic lapses of memory (8 out of 27). A similar trend was observed in the General Practice Group (P< 0.3). No association was observed between dose omission and other variables such as sex, age, number of doses per day and number of tablets per day, using chi squared analysis. Omissions were no more frequent among those receiving more than one drug compared to those on single-drug therapy.
Saliva phenytoin concentration The mean + s.e. mean saliva phenytoin concentration in the Hospital Group was 1.02± 0.12 g mli', compared to 0.68 + 0.12 Lg mli' in the General Table 2 Nature of anticonvulsant therapy
Hospital
Therapy Phenytoin alone Phenytoin and phenobarbitone Phenytoin and primidone Other drugs
General Practice
group
group
(n =50)
(n=36)
18
8
17
23
12 8
4 2
ANTICONVULSANT THERAPY
Practice Group. This difference is statistically significant (P
COMPLIANCE WITH ANTICONVULSANT THERAPY IN A HOSPITAL CLINIC AND IN THE COMMUNITY J.C. MUCKLOW & C.T. DOLLERY Department of Clinical Pharmacology, Royal Postgraduate Medical School, London W1 2 OHS 1 Seizure control, saliva anticonvulsant concentration, prescribing habits and compliance with anticonvulsant medication have been compared in 86 epileptic subjects attending either a specialist hospital clinic or general practice surgeries. 2 Of all subjects experiencing recurrent seizures 7096 had saliva concentrations of phenytoin below the range equivalent to the 'therapeutic range' of plasma concentration. Mean saliva phenytoin concentrations did not differ significantly between the two treatment settings and were low largely because of the low mean dosage prescribed. 3 Eleven subjects in all had no detectable phenytoin in their saliva and could clearly be identified as noncompliant. Freedom from seizures appeared to predispose to poor compliance in these subjects as well as among those admitting repeated omission of doses.
Introduction
Methods
Seizure control amongst epileptic subjects receiving anticonvulsant therapy is known to be influenced by the treatment setting and this is partly due to differences in patient compliance. Kutt, Haynes & McDowell (1966) found that unreliable drug intake was responsible for apparent refractoriness to phenytoin therapy in twelve out of sixteen out-patients studied. Gibberd, Dunne, Handley & Hazleman (1970) reported significantly lower plasma concentrations of phenytoin among out-patient epileptics than among in-patients. Supervision of drug taking in both these studies led to increased plasma phenytoin and improved seizure control. Plasma concentration of phenytoin is a wellestablished guide to drug dosage in epileptic subjects and correlates well with control of seizures (Buchthal, Svensmark & Schiller, 1960) but the need for venepuncture limits the wide use of this measurement. Saliva phenytoin concentrations provide a reliable index of concentration in plasma (Bochner, Hooper, Sutherland, Eadie & Tyrer, 1974) and this is also true of phenobarbitone (Cook, Amerson, Poole, Lesser & O'Tuama, 1975). The majority of epileptics do not attend hospital clinics on a regular basis and their anticonvulsant therapy is supervised by a general practitioner. Our stjdy was designed to compare seizure control, saliva phenytoin concentration, prescribing habits and compliance with medication in the context of hospital out-patient clinic and general practice surgery.
The study involved 86 epileptic patients, 50 of whom attended a Neurology Clinic at Hammersmith Hospital and 36 whose anticonvulsant therapy was supervised by general practitioners in the North Hammersmith District (these two groups will be referred to as the Hospital Group and the General Practice Group). The overall sample age range was 12-75 years. There were equal numbers of males and females in the Hospital Group while the General Practice Group comprised 21 males to 15 females. All patients were receiving phenytoin sodium (as capsules or sugar-coated tablets) and the majority were having one or more additional anticonvulsant drugs. Treatment had in every case been instituted at least 3 months prior to involvement in this study. Each patient's drug regime was recorded precisely by the doctor on a questionnaire. The name of each drug, tablet size, number of tablets per day and timing of each dose were recorded. The number of seizures experienced during the preceding 3 months was also entered. Carefully-worded questions were then asked by the doctor about compliance with therapy (see Figure 1). The exact timing of the last dose of phenytoin was recorded. All patients were weighed. At least 3 ml of mixed saliva were collected from each patient after allowing a single 25 mg tablet of ascorbic acid to dissolve in the mouth. Tongue and cheek movements provided a further stimulus for salivary flow. The sample, in a 'Sterilin' plastic container, was stored frozen. After thawing, the saliva was centrifuged for 10 min at 1800 rev/min and the' concentrations of phenytoin and phenobarbitone in
.* Present address: Department of Pharmacological Sciences, University of Newcastle-upon-Tyne, NE1 7RU
76
J.C. MUCKLOW & C.T. DOLLERY
How often do you forget to take a dose of phenytoin
majority (67%) were receiving phenytoin and phenobarbitone either separately or in combined preparations. In neither group was seizure control significantly better amongst patients taking more than one anticonvulsant drug. All patients were taking their drugs in at least two divided doses each day. If all drugs (anticonvulsant and others) were considered, 64% of the Hospital Group and 80.6% of the General Practice Group were taking three or more doses each day and more than half of all patients were taking six or more tablets each day. The mean daily doses (in mg/kg) of phenytoin, phenobarbitone and primidone did not differ significantly between the two groups (Table 3).
or phenobarbitone?
Never Occasionally Once or twice a week Every other day Every day At what time of day are you most likely to forget?
Morning Midday Evening Bedtime Other
Omission of doses (Table 4)
Nature of questions asked about Figure 1 compliance.
the supernatant were measured, using the gas chromatographic method of MacGee (1976) as modified by Vajda, Williams, Davidson, Falconer & Breckenridge (1974). Statistical analyses were performed using Student's unpaired t-test and chi-squared test.
Results
The mean age was 32 years in the Hospital Group and 37.6 years in the General Practice Group. Of the Hospital Group 52% and of the General Practice Group 64% had been free from seizures during the 3 months preceding the study (Table 1).
Anticonvulsant therapy
Therapeutic regimens varied considerably in the Hospital Group (Table 2) and only 36% were receiving phenytoin alone. The remainder were also taking phenobarbitone and/or primidone. A small number were also receiving other drugs such as carbamazepine, sodium valproate, acetazolamide and ethosuximide. In the General Practice Group the Table I Number of patients having seizures in preceding 3 months
Hospital Seizures No seizures Total
group
General Practice group
24 26 50
13 23 36
54% of patients in the Hospital Group and 50% in the General Practice Group admitted omitting doses at least occasionally. However, only five patients admitted to missing a dose more than once or twice a week. Although the midday dose was the one most commonly omitted, a substantial number in each group confessed to forgetting either the morning or the evening dose from time to time. In no patient did the occurrence of side effects appear to contribute to poor compliance. In the Hospital Group there was a significantly greater (P< 0.01) incidence of seizures (16 out of 23) amongst those patients who denied omitting doses at any time than amongst those who confessed periodic lapses of memory (8 out of 27). A similar trend was observed in the General Practice Group (P< 0.3). No association was observed between dose omission and other variables such as sex, age, number of doses per day and number of tablets per day, using chi squared analysis. Omissions were no more frequent among those receiving more than one drug compared to those on single-drug therapy.
Saliva phenytoin concentration The mean + s.e. mean saliva phenytoin concentration in the Hospital Group was 1.02± 0.12 g mli', compared to 0.68 + 0.12 Lg mli' in the General Table 2 Nature of anticonvulsant therapy
Hospital
Therapy Phenytoin alone Phenytoin and phenobarbitone Phenytoin and primidone Other drugs
General Practice
group
group
(n =50)
(n=36)
18
8
17
23
12 8
4 2
ANTICONVULSANT THERAPY
Practice Group. This difference is statistically significant (P
