Over-the-counter medicines and the potential for unwanted sleepiness (No.24)

Chapter 5:
Opioid Analgesics and Antimotility Drugs

There are four opioid compounds available OTC which are antimotility drugs, three of which are also used as analgesics. They are codeine, dihydrocodeine, morphine (opioid analgesics) and loperamide. There are twenty-eight medicines available containing these substances. Codeine and dihydrocodeine are morphine-like substances, and are classed as weak opioid agonists, as both their analgesic and unwanted effects are much less than those of morphine. Loperamide is a pethidine congener and is only used for its action in the gut. All of these drugs penetrate the blood brain barrier into the CNS and are all stated to have drowsiness as a side effect. Table 5.1 summarises the medicines available OTC containing opioids. The recommended dosage and labelling of medicines that we purchased are also summarised.

Table 5.1 is available as an MS Word download from the foot of this page.

Codeine

We have identified 14 medicines available OTC that contain codeine. These are Boots Migraine Relief, Boots Tension Headache Relief (also contains doxylamine), Cocodamol, Codis 500, Feminax (also contains hyoscine), Migraleve (also contains buclizine), Panadeine, Panadol Ultra, Paracodol, Propain, Solpadeine, Solpadeine Max, Syndol and Veganin. They are all used for the treatment of mild to moderate pain. The BNF recommended dose for codeine is 30-60mg every four hours when necessary, to a maximum of 240mg daily. However, the three medicines we looked at had dosages below this recommended dose:

Migraleve (also contains buclizine in the pink tablets) 16mg per dose, maximum daily dose of 64mg.

Solpadeine Max 25.6mg per dose, maximum daily dose of 102.4mg.

Veganin 13.6mg per dose, maximum daily dose of 54.4mg.

The BNF recommends warning label number two: Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.

Structure and Function

In most OTC medicines codeine is in the form of codeine phosphate. It is a centrally acting analgesic that is habit forming and has the potential for abuse. Codeine is readily absorbed from the gastrointestinal tract and distributes around the body to various tissues. It crosses the blood brain barrier, easily penetrating the CNS. Codeine is toxic at doses above 240mg.

Pharmacokinetics

The majority of studies investigating the Pharmacokinetics of codeine use doses higher than the recommended doses for OTC medicines. One study investigated the Pharmacokinetics of continuous codeine administration over a two and a half-day period. Initially 60mg of codeine was administered every four hours for the first three doses, and 30mg was administered every four hours thereafter for twelve doses. After the first 60mg dose a maximum plasma concentration of 138.8 ± 59.4 ng/ml was reached after 1.1 ± 0.6 hours. An elimination half-life of 2.6 ± 0.9 hours was calculated (Band et al., 1994). In the same study, steady-state pharmacokinetic data were calculated after the subjects had completed the course of administration. A steady-state maximum plasma concentration of 222.9 ± 48.9 ng/ml was obtained 1.1 ± 0.3 hours (post-second dose). A slightly slower elimination half-life of 2.3 ± 0.7 hours was calculated. Elimination of codeine is primarily via the kidneys and around 90% of a single dose is excreted within 24-hours.

Sedation and effects on Performance

Although the BNF recommends warning labels for drowsiness on codeine packaging, very few studies have found sedating effects with codeine. The study by Band et al. (1994) found that eight out of the 13 subjects experienced sleepiness at some point in the study; however, this may be due to the fact that they were administered codeine at 11pm, 3am and 7am, so they had a disturbed nights sleep. Another study found that administration of up to 60mg of codeine had no detectable sedative activity (Redpath & Pleuvry, 1982).

Studies investigating the effect of codeine on performance all found that, generally, codeine did not impair performance. However, each study did find that codeine affected specific tasks. In one study, administration of 100mg codeine failed to affect performance in objective tests administered 90 minutes post-dose. These tests included body sway, digit symbol substitution, flicker fusion and Maddox wing. However, subjectively they did find that 100mg codeine did make participants mentally slow (Saarialho-Kere et al., 1986). A more recent study also found that 60mg and 120mg of codeine did not impair performance. Mild subjective effects on mood were found, but these appeared not to be dose related (Walker & Zacny, 1998). One study did find slight impairment of visuo-motor coordination after administration of both 60mg and 90mg of codeine. Dynamic visual acuity was also found to be impaired but only after the 90mg dose (Bradley & Nicholson, 1986). The authors suggest that impairment of neuromuscular function, and not sedation, is the likely cause of any performance impairment seen.

Dihydrocodeine

There are only two drugs available OTC that contain dihydrocodeine. These are Boots Dental Pain Relief and Paramol. They are both used for the treatment of moderate to severe pain. The recommended dosage stated by the BNF is 30mg every four to six hours when necessary. However, the recommended dose of Paramol is one or two tablets (7.46- 14.92mg) every four to six hours, with a maximum of eight tablets (59.68mg) in any 24-hour period. The BNF recommends warning label number two: Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.

Structure and Function

Dihydrocodeine is pharmacologically very similar to codeine, and has no substantial advantages or disadvantages (apart from cost) over codeine.

Pharmacokinetics

Rowell et al. (1983) reported that oral administration of 30mg dihydrocodeine produces a peak plasma concentration of 71.8 ± 11.8 µg/l, 1.60 ± 0.12 hours post-dose. In the same study, administration of 60mg dihydrocodeine produced a peak plasma concentration of 146 ± 20.7 µg/l, 1.82 ± 0.11 hours post-dose. Elimination half-lives ranged from 3.3-4.5 hours. Renal dysfunction alters the Pharmacokinetics of dihydrocodeine by increasing the time to peak plasma concentration and reducing the rate of clearance, thus increasing the overall duration of action of the drug (Barnes et al., 1985). Despite these findings, age does not appear to alter the Pharmacokinetics of single oral doses of dihydrocodeine (Davies et al., 1989). In the same study and after multiple dosing of dihydrocodeine, there was a significant increase in maximum plasma concentration in the elderly.

Sedation and effects on Performance

We found very little literature relating to the effect of dihydrocodeine on sedation and performance impairment. One paper that assessed performance, looked at the effect of 20mg dihydrocodeine by subcutaneous injection for the relief of tourniquet pain. The dihydrocodeine did not impair performance of a symbol cancellation test, which measures attention (Szekely et al., 1986). Another more recent paper looked at the effect of administering 90mg dihydrocodeine. There was no significant impairment to several performance tasks, including digit symbol substitution, critical flicker fusion and choice reaction time. The authors also found no significant increase in sedation compared to placebo after the dihydrocodeine administration (Webb & Kamali, 1998).

Loperamide

There are seven medicines available OTC that contain loperamide. They are Arrett Capsules, Boots Diareze, Diasorb, Diocalm Ultra, Imodium (including Imodium Liquid), Imodium Plus and Normaloe. These are all treatments for the rehydration in acute and chronic diarrhoea in adults. The BNF recommended dose for acute diarrhoea is 4mg initially followed by 2mg after every loose stool for up to five days. The usual dose is 6-8mg daily, maximum dose of 16mg daily. For the treatment of chronic diarrhoea the recommended dose is 4-8mg daily in divided doses, subsequently adjusted according to the response. Maximum dose of 16mg daily. Drowsiness is stated as a side effect of loperamide; however, there is no warning label recommend by the BNF.

Structure and Function

Loperamide has a relatively selective action on the gastrointestinal tract. Around 85% of administered loperamide can be found in the gut. It was approved for non-prescription use in 1988 (Litovitz et al., 1997).

Pharmacokinetics

We found one study that investigated the Pharmacokinetics of loperamide. Administration was a single 8mg dose in either capsule or syrup form. Peak plasma concentrations were reached 5.2 ± 0.3 hours and 2.4 ± 0.7 hours for the capsules and syrup respectively. Elimination half-lives of 11.2 ± 0.8 hours and 10.2 ± 0.6 hours respectively, were calculated. Approximately 1% of the dose was excreted as unchanged loperamide in urine (Killinger et al., 1979).

Sedation and effects on Performance

There is little literature available on the effect of loperamide on sedation and performance. The BNF states drowsiness as a side effect. The insert/packaging of Imodium Plus also states this; however, there are no warning labels on the exterior packaging. We found one paper that analysed 216 poison centre reports on the over-ingestion of loperamide. The most common symptom seen was drowsiness, with 15.7% of the cases reporting it as a side effect (Litovitz et al., 1997).

Morphine

We have identified five OTC medicines containing morphine. They are Diocalm, Enterosan, J. Collis Brownes Mixture, Kaolin and Morphine Mixture and Opazamines. The BNF does not state a recommended dosage, however below are the recommended doses for three of the medicines:

Diocalm Two tablets (0.79mg) every two to four hours as required. Up to a maximum of 12 tablets (4.74mg) in 24 hours.

J. Collis Brownes Mixture Two to three 5ml spoonfuls (10-15ml; 2-3mg). May be repeated once or twice at four hourly intervals if required (difficult to interpret).

Kaolin and Morphine Mixture Two 5ml spoonfuls (10ml; 0.916mg). Repeat up to three times a day if required.

The BNF recommends warning label number two: Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink.

Structure and Function

Morphine is effective in most kinds of acute and chronic pain; however, all the drugs sold OTC containing morphine are antimotility medicines for the treatment of acute diarrhoea. It increases the tone and rhythmic contractions of the intestine but diminishes propulsive activity and its overall effect is constipating (Rang et al., 1995). Regular administration of morphine can lead to both tolerance and dependence.

Pharmacokinetics

There were very few pharmacokinetic studies on administration of low doses of oral morphine, i.e. those equivalent to OTC medications. One study looked at the administration of 20mg morphine in oral slow-release form. A mean peak plasma concentration of 14.8ng/ml occurred two hours twenty two minutes post-administration (Vater et al., 1984). Administration of oral solution morphine (non-slow release) normally reaches a peak plasma concentration around 45 minutes post-dose (Hoskin et al., 1989). The elimination half-life of morphine in healthy adults is between three and four hours (Rang et al., 1995). The elderly often display reduced clearance rates and increased maximum plasma concentrations (Baillie et al., 1989); again, this is probably due to renal dysfunction rather than ageing per se.

Sedation and effects on Performance

Morphine is a well-known sedative, it is used in higher concentrations to treat severe acute and chronic pain and its sedative action aids its analgesic effect. Searching for literature on the subject of sedation and performance was unproductive for the low doses of morphine available OTC. One paper that investigated the actions of sustained release morphine on severe non-malignant pain found that performance on perceptual and cognitive tasks was improved, although sedation levels increased. The authors concluded that this performance improvement was probably due to the removal of pain as a mental stressor (Lorenz et al., 1997).

Conclusions

Morphine is well known as a sedating painkiller; however, from the literature we were unable to identify the dose at which morphine begins to have these effects. The recommended dose of morphine on OTC medicines is very low. However, morphine has the potential for dependence and abuse. The availability of these medicines OTC leaves them more open to wrongful use and therefore administration above the recommended dose.

Codeine and dihydrocodeine are derivatives of morphine. The literature stated that the chance of sedation and performance impairment is very low. At the recommended doses of OTC medicines containing these substances, there is little chance of people being affected in this way. However, as with morphine there is a small potential for dependence; when this occurs, administration of these substances excessively above the recommended dose may lead to impairment.

Although there was little literature on loperamide, from the one paper we did find, high doses could cause sedation. If there is any possibility of sedation occurring then there is a need for labelling on packaging (at present no warning is recommended). As with most medication, caution should be taken with the elderly as enhanced effects of these drugs are likely to occur.

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