ASA Adjudication on Crookes Healthcare Ltd

Ad

A TV ad for the painkiller Nurofen Plus featured a man sawing and a woman lifting heavy bags out of a car. The voice-over said "There's pain and there's pain plus". The woman was shown holding her back, as the voice-over continued "Nurofen Plus has the targeted relief of Nurofen tablets plus the added strength of a second painkiller to fight pain and bring you fast, powerful pain relief". Another woman was shown lifting a squash racquet out of a car and then hitting a squash ball with force. The voice-over and text on the screen stated "Nurofen plus. No stronger painkiller without prescription".

Issue

The Over The Counter Drugs Information and Advice Agency challenged whether the ad was misleading, because they believed another painkiller called Paramol was stronger than Nurofen Plus.

BCAP TV Code

Response

Crookes Healthcare Ltd (Crookes) said the ad complied with the advertising guidelines issued by the Proprietary Association of Great Britain (PAGB), and had been approved by them. They said, under those guidelines, the claim "No stronger painkiller without prescription" was classed as a top parity claim, which meant that there were no other products that contained higher levels of the active ingredients found in the formulation, and that no other formulations had been found to be more effective.

Crookes explained that they had undertaken a full literature search and found no standard, recognised, published direct conversion tables comparing the oral ibuprofen codeine (Nurofen Plus) with the oral paracetamol dihydrocodeine (Paramol) combinations. They said they had been unable to identify any papers that discussed the bioavailability and therapeutic index directly comparing oral codeine against oral dihydrocodeine gram for gram in a clinical setting in peer-reviewed journals. However, Crookes argued that the Oxford Textbook of Medicine made an approximation of codeine and dihydrocodeine based on their equivalence to oral morphine. They submitted a copy of the equivalence table  published in the Oxford Textbook of Medicine, and argued that the table showed no differences between those two ingredients when compared with morphine, because both had a potency ratio of 1/10 and an efficacy duration of between three and six hours.

Crookes said the Scottish Intercollegiate Guidelines Network (SIGN), an internationally recognised and independent advisory group, had given expert recommendation on the control of pain, which also suggested no difference between codeine and dihydrocodeine. They explained that SIGN had listed both codeine and dihydrocodeine on 'step 2' of the World Health Organisation's (WHO) 'pain ladder' model of pain management, which was used to recommend the use of analgesics including opioids such as codeine and dihydrocodeine. Crookes submitted copies of both these documents, and pointed to SIGN's advice that "At therapeutic doses there is no evidence of superiority of one opioid for mild to moderate pain over another. In clinical practice it appears that codeine and dihydrocodeine are equipotent". Crookes argued that, on that basis, the 76.8 mg of codeine per maximum dose contained in Nurofen Plus would be more efficacious than the 59.6 mg of dihydrocodeine per maximum dose contained in Paramol.

Crookes commented on a scientific study cited by the complainant, which appeared to show that dihydrocodeine was stronger than codeine. They argued that that was an early study in which the opiate was administered by intravenous injection to animals, and was therefore not relevant to the present investigation which concerned oral administration to humans. They said, as oral tablets, the bioavailability of both Nurofen Plus and Paramol in humans would be subject to the effects of 'first pass metabolism'. They explained that that was when a drug, taken orally, was broken down (or metabolised) by the digestive system and enzymes in the liver. If a large portion of a drug was metabolised in that way, then only a small portion of the drug would be available to be absorbed into the body.

Crookes said one of the strengths of codeine as an analgesic was that it was very resilient at first pass metabolism. Crookes submitted evidence from the Martindale Complete Drug Reference guide (Martindale), which demonstrated that codeine was protected from rapid first pass metabolism and had a high oral/intramuscular analgesic relative potency of 60%. In contrast, Martindale showed that dihydrocodeine experienced substantial first pass metabolism activity in the gut wall and liver, resulting in a bioavailability of 20%. Crookes argued that, because dihydrocodeine was less bioavailable than codeine, it would also be less efficacious, gram for gram, than codeine.

Crookes said, although they had not identified any studies that directly compared combinations of ibuprofen codeine with paracetamol dihydrocodeine, one peer-reviewed study had compared the efficacy of an oral ibuprofen codeine combination with an oral paracetamol codeine caffeine product. They submitted a copy of the study and pointed to the summary, which stated "the ibuprofen combination produced significantly greater analgesia than the paracetamol combination". Crookes argued that it may be possible to conclude that, on that basis, the ibuprofen codeine combination would be more efficacious than the paracetamol dihydrocodeine combination.

Crookes also submitted a copy of a study which compared the efficacy of oral ibuprofen, paracetamol and dihydrocodeine from systematic reviews of randomised double-blind trials. The comparisons were made using a standard measure of patients gaining at least 50% pain relief and the Number of patients Needed to Treat (NNT) was calculated. They said this study showed that ibuprofen 400 mg had a NNT of less than 2.4, meaning that 60 - 70% of patients had pain relief with 400 mg of ibuprofen. This was compared to 1000 mg of paracetamol, which had a NNT of 3.7, meaning that 40% of patients obtained pain relief using 1000 mg of paracetamol. Crookes pointed out that dihydrocodeine 30 mg gave benefit to only 16% of patients using the standard measure, which was considered very low. Crookes argued that, as ibuprofen appeared to be superior to dihydrocodeine in randomised controlled trials, there was no evidence to suggest that an ibuprofen codeine combination (Nurofen Plus) was inferior to a paracetamol dihydrocodeine combination (Paramol).

Clearcast (formerly the Broadcast Advertising Clearance Centre) said they had sought confirmation from Crookes that the top parity claim made in the ad was true. They said Crookes had conducted several searches and also sought confirmation from the Medicine and Healthcare products Regulatory Agency (MHRA), and had verified that their claim was still valid.

Assessment

Not upheld

The ASA noted that Crookes had complied with the PAGB's advertising guidelines and that the top parity claim made in the ad had been approved by them. We also noted that Crookes had carried out a full literature search and found no recognised, well-established conversion tables for comparing the particular ibuprofen codeine and paracetamol dihydrocodeine combinations under investigation. However, we acknowledged that the Oxford Textbook of Medicine stated that there was "nothing to choose between codeine ... and dihydrocodeine in terms of efficacy". We also acknowledged that this view was supported by SIGN, and that codeine and dihydrocodeine were given equivalence on WHO's 'pain ladder' model. We considered that the larger amount of codeine contained in the maximum dose of Nurofen Plus (76.8 mg), compared to the amount of dihydrocodeine contained in the maximum dose of Paramol (59.6 mg), indicated that Nurofen Plus would be more effective in relieving pain.

We considered that that was reinforced by the studies submitted by Crookes, which showed that oral codeine was more resilient at first pass metabolism, and therefore had a greater bioavailability, than oral dihydrocodeine. We understood that meant that, in contrast to oral codeine, oral dihydrocodeine suffered a significant reduction in the absorption of its active component into the body. On that basis we considered that the 76.8 mg of codeine in Nurofen Plus would be more easily absorbed into the body, and would therefore be more efficacious, than the 59.6 mg of dihydrocodeine contained in Paramol.

We noted that Crookes provided copies of other randomised, double-blind studies designed to measure and compare the analgesic efficacy of ibuprofen with paracetamol, and in one case with dihydrocodeine. We acknowledged that one study concluded that "an ibuprofen codeine combination produced better analgesia than a paracetamol codeine caffeine combination", and another that "ibuprofen is a better choice than dihydrocodeine". We considered that, in those randomised, controlled trials, ibuprofen appeared superior to both paracetamol and dihydrocodeine. We also considered that, because codeine was more bioavailable than dihydrocodeine, the oral ibuprofen codeine combination in Nurofen Plus would be more effective than the oral paracetamol dihydrocodeine combination in Paramol. We therefore concluded that the top parity claim "No stronger painkiller without prescription" was unlikely to mislead.

We investigated the ad under CAP (Broadcast) TV Advertising Standards Code rules 5.1 (Misleading advertising), 5.2.1 (Evidence), 5.4.6 (Comparative advertising) and 8.1.1 (Medicines, treatments, health claims and nutrition assessment of claims) but did not find it in breach.

Action

No further action necessary.

Adjudication of the ASA Council (Broadcast)