Anaesthesia, 199 1, Volume 46, pages 91 5-9 17
`
`Analgesic efficacy of controlled-release dihydrocodeine
`
`A comparison of 60, 90 and 120 mg tablets in cold-induced pain
`
`H. A. WOTHERSPOON, G. N. C. KENNY AND C. S. McARDLE
`
`Summary
`A prospective, double-blind, single-dose placebo-controlled four-part crossover study of 12 healthy volunteers was carried out to
`compare the analgesic eficacy of controlled-release dihydrocodeine tablets 60, 90 and I20 mg (DHC Continus tablets, Napp
`Laboratories) in cold-induced pain. Subjects received each of the four treatments in a random order using a latin square design.
`On each of the four study days, the volunteers performed cold pressor tests, before dose and again at 4 , 8 and 12 hours after dose.
`Subjects rated their pain continuously over a 120-second period using a visual analogue scale. At 4 hours there was a significant
`reduction in pain in subjects who received 120 mg or 90 mg tablets compared with placebo, and in subjecfs who received 120 mg
`tablets compared with those who received 60 mg tablets. At 8 hours, 120 mg and 90 mg dihydrocodeine were still better than
`placebo. There was no significant diference in side effects between treatments.
`
`Key words
`Analgesics; dihydrocodeine.
`Pain: cold-induced.
`
`Dihydrocodeine is an opioid analgesic which has been
`shown to be effective in the treatment of moderately severe
`pain.'-' Until recently, it was only available in injectable
`form or as a normal release tablet formulation. In 1988 a
`new controlled-release oral preparation of dihydrocodeine
`60 mg, designed for twice daily dosing, was developed.
`The analgesic efficacy of controlled-release dihydroco-
`deine 60 mg tablets and normal release dihydrocodeine
`30 mg tablets was examined in patients with chronic back
`pain and in patients with osteoarthritis of the weight-
`bearing joints. This study demonstrated that controlled-
`release dihydrocodeine 60 mg tablets administered twice
`daily was as effective as the normal release preparation
`given as 30 mg four times daily.4 The efficacy of controlled-
`release dihydrocodeine 60 mg in comparison with normal
`release dihydrocodeine 30 mg was further evaluated in 90
`patients following sternotomy. A patient-controlled anal-
`gesia system was used to supplement the dihydrocodeine,
`and morphine requirements were significantly reduced with
`both active preparations compared to p l a c e b ~ . ~
`Further to this work, controlled-release dihydrocodeine
`tablets 90 mg and 120 mg have been developed for evalua-
`tion. The aim of this study was to assess the relative
`analgesic efficacy of controlled-release dihydrocodeine 60,
`90 and 120 mg compared with placebo using cold-induced
`pain6 in healthy volunteers.
`
`Methods
`Healthy male volunteers aged between 18 and 40 years who
`had undergone preliminary screening (including history,
`physical examination, haematological and biochemistry
`testing, 12-lead ECG recording and narcotic screening)
`were entered into the study. Subjects with a history of
`sensitivity to dihydrocodeine, chronic alcohol abuse or
`those known to smoke were excluded. Subjects who had
`taken prescribed medication within the 4 weeks before the
`study or any 'over the counter' medication within 48 hours
`of the start of the study were not eligible.
`In order to familiarise subjects with the cold-pressor test,
`a minimum of four training sessions were completed, two
`sessions on each occasion, separated by approximately 3
`days. All tests were performed with the subjects sitting in a
`quiet room with no external interferences. Room tempera-
`ture was kept at 20°C (SD 2°C). There were no clocks in
`the room and no wrist watches were allowed.
`Subjects placed their non-dominant hand up to the ulnar
`prominence in a thermostatically controlled water bath at
`3 T C k 1°C. After 2 minutes, they transferred their hand
`into a water bath at 3"C+OS0C. Over the next 120
`seconds they rated their pain continuously using a hand-
`controlled paddle linked to a visual analogue scale (VAS)
`displayed on a computer monitor. The scale ran from 0 to
`
`H.A. Wotherspoon, BN, MSc, Research Nurse, C.S. McArdle, MD, FRCS, Consultant Surgeon, University Department of
`Surgery, G.N.C. Kenny, BSc, MD, FFARCS, Senior Lecturer, University Department of Anaesthesia, Royal
`Infirmary, 8-16 Alexandra Parade, Glasgow G31 2ER.
`Accepted 4 February 1991.
`
`0003-2409/91/110915+03 %03.00/0
`
`@ 1991 The Association of Anaesthetists of Gt Britain and Ireland 915
`
`1
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`

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`916
`
`H.A. Wotherspoon, G.N.C. Kenny and C.S. McArdle
`
`10 where 0 corresponded to no pain and 10 represented
`maximum pain. The VAS pain scores, recorded at 2-second
`intervals over the 120-second period, were stored on
`computer disk. After 120 seconds, they removed their hand
`from the water.
`Successive cold pressor tests were checked for reproduci-
`bility and, if necessary, further tests were carried out until
`readings were consistent. A maximum of eight training
`sessions per subject were permitted. Those who demon-
`strated reproducible baseline pain values were entered into
`the study, commencing 3-10 days after the last training
`session
`Subjects were instructed to fast from 2300 hours on the
`previous day, abstain from any methylxanthine-containing
`foods and drinks such as tea, coffee, cola and chocolate for
`12 hours and abstain from alcohol for 24 hours before each
`study. During each study day, subjects received a standard
`lunch 4 hours after the test medication had been admini-
`stered and a standard dinner 6 hours later.
`Subjects were allocated to receive the four treatments
`(placebo, 60 mg, 90 mg, 120 mg) in a random order using a
`latin square design to control for order effects. Each treat-
`ment period consisted of one day with a minimum of 3
`days and a maximum of 10 days between treatments. In
`order to maintain the double-blind design of the study,
`subjects were given one tablet of the test medication and
`matching placebo tablets of the two alternative strengths
`(or placebos of all three) at approximately 0900 hours on
`each of the four study days (Table 1). On each day four
`cold pressor tests were carried out; the initial test was
`performed before ingestion of the tablets and then repeated
`at 4, 8 and 12 hours. Volunteered symptoms and side
`effects were documented before each test.
`The pain scores recorded at 0, 4, 8 and 12 hours after
`treatment were compared using the area under the pain
`score versus time curve (AUC). The AUC values up to 2
`minutes were compared to give an indication of the total
`amount of pain experienced by the volunteer during the
`cold pressor test.
`Before medication the AUC values varied from day to
`day. To compensate for this, the analysis was carried out
`on the ratio of the AUC to the baseline (0 hours) for each
`treatment. Repeated measures analysis of variance was
`used to detect any treatment effects on the AUC ratio. The
`least significant difference method was used to compare the
`mean AUC ratio for any two treatments. The least signifi-
`cant difference is the smallest difference between any two
`treatment means that would be statistically significant
`when one adjusts for the multiple comparisons involved.
`Fisher's exact test was used to compare the frequency of
`reporting side effects of the two extreme treatments
`(placebo and 120 mg tablets) and if a difference was seen,
`the other pairs were compared. All statistical tests were
`carried out at the 5% significance level.
`
`Results
`Thirteen subjects were eligible for the study, but one volun-
`teer withdrew after two training sessions. Twelve volun-
`teers, therefore, completed the study.
`The mean AUC ratio and standard deviation of each
`treatment group at 4 hours after treatment are shown in
`Table 2. The AUC ratio for both the 90 mg and 120 mg
`tablets was significantly different to that of placebo. In
`
`Table 1. Treatment administration.
`
`Group
`
`60 mg
`90 mg
`120 mg
`Placebo
`
`60 mg
`
`Active
`Placebo
`Placebo
`Placebo
`
`90 mg
`
`Placebo
`Active
`Placebo
`Placebo
`
`120 mg
`
`Placebo
`Placebo
`Active
`Placebo
`
`Table 2. Ratio of the area under pain score versus time curve
`(AUCratio) 4 hours after dose.
`
`Treatment
`
`Placebo
`DHC 60 mg
`DHC 90 mg
`DHC 120 mg
`
`12
`12
`12
`12
`
`96.1
`89.3
`86.6
`78.4
`
`8.64
`14.04
`12.30
`18.32
`
`The least significant difference was 9.2, so that the following
`comparisons were statistically significant: DHC 120 mg vs
`placebo; DHC 120 mg vs DHC 60 mg; DHC 90 mg vs placebo.
`
`Table 3. Ratio of the area under pain score versus time curve
`(AUCratio) 8 hours after dose.
`
`Treatment
`
`Placebo
`DHC 60 mg
`DHC 90 mg
`DHC 120 mg
`
`n
`
`12
`12
`12
`12
`
`Mean
`
`99.3
`89.2
`83.4
`82.7
`
`SD
`
`17.70
`15.10
`11.83
`19.83
`
`The least significant difference was 11.7, so that the following
`comparisons were statistically significant: DHC 120 mg vs
`placebo; DHC 90 mg vs placebo.
`
`Table 4. Ratio of the area under pain score versus time curve
`(AUCratio) 12 hours after dose.
`
`Treatment
`
`Placebo
`DHC 60 mg
`DHC 90 mg
`DHC 120 mg
`
`n
`
`12
`12
`12
`12
`
`Mean
`
`95.1
`87.3
`91.7
`87.4
`
`SD
`
`26.54
`14.90
`18.92
`14.60
`
`The least significant difference was 11.4, so that no significant
`treatment effects were observed.
`
`addition, the AUC ratio for the 120 mg tablets was signifi-
`cantly different to that of the 60 mg tablets. At 8 hours
`after treatment the AUC ratio for both the 90 mg and
`120 mg tablets was again significantly different to that of
`the placebo (Table 3). At 12 hours after treatment no
`significant treatment difference was observed (Table 4).
`Drowsiness and headache were
`the most frequently
`reported side effects, but the difference between 120 mg
`tablets and placebo was not significant for either symptom.
`
`Discussion
`In the assessment of analgesics, experimental models
`applying a painful stimulus to healthy volunteers have
`proved
`to be of value. Furthermore,
`the laboratory
`environment facilitates
`the study of
`the dose-effect
`relationship using a crossover design under controlled,
`double-blind conditions.' The cold pressor test6,8-'0 has
`
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`

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`Analgesic eficacy of controlled-release dihydrocodeine
`
`917
`
`proven sensitivity and has previously demonstrated varia-
`tions between different analgesics and, indeed, between
`different strengths of analgesics." In this study we used the
`cold pressor test to assess the relative analgesic efficacy of
`three strengths of controlled-release dihydrocodeine tablets
`(60 mg, 90 mg and 120 mg) compared with placebo tablets.
`The time for controlled release dihydrocodeine 60 mg
`and 120 mg to reach peak serum levels is 4 hours.14 At 4
`hours and 8 hours after administration of the study medi-
`cation a clear difference in the AUC ratios was observed
`between all three strengths of controlled-release dihydroco-
`deine and placebo; the differences between 120 mg and
`placebo and 90 mg and placebo were significant. At 4
`hours, the difference between 120 mg and 60 mg was also
`significant. At 12 hours after treatment all three strengths
`of controlled-release dihydrocodeine decreased the total
`pain experienced by the volunteers but no significant differ-
`ences were seen between strengths.
`Drowsiness and headache were the most common of the
`side effects reported. The majority of all the reported side
`effects were classified as mild in nature. There was a higher
`frequency of drowsiness and headache after administration
`of controlled-release dihydrocodeine 120 mg compared to
`the two lower strengths of dihydrocodeine and placebo,
`although this was not statistically significant.
`In conclusion, this study has shown that there was a clear
`dose-response
`relationship between controlled-release
`dihydrocodeine 60 mg, 90 mg and 120 mg; proportionately
`greater analgesia was obtained with the 90-mg and 120-mg
`strengths compared to the 60-mg tablet. These results
`confirm that controlled-release dihydrocodeine 90 mg and
`120 mg are effective analgesics in the control of severe pain.
`
`Acknowledgments
`The authors thank Dr J. Posner (Wellcome Laboratories)
`for his help with the study methodology, Gillian Reid,
`Senior Clinical Research Associate and also Napp
`
`Laboratories Ltd., for financial assistance and supplies of
`study drugs.
`
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