FormalPara Key Summary Points

Sixteen placebo-controlled studies that involved 3378 subjects suffering from acute pain were analyzed for the efficacy of low-dose codeine (≤ 30 mg) combination products.

Twenty randomized clinical trials which included at least one dose of codeine (from 30 to 240 mg daily), were analyzed for the safety and adverse-effects profile.

In EudraVigilance database for the 10-year time period, a total of 20 individual case safety reports for dependence were identified with codeine as a suspect drug.

Low-dose codeine in fixed combinations with other drugs is effective and safe when used as recommended.

There is no exact proof in the available literature that clearly links low doses of codeine to substance use disorder issues in non-dependent subjects.

Introduction

Codeine or 3-methylmorphine is a mild opioid with analgesic and antitussive effect [1]. Its analgesic activity is mostly due to the conversion to morphine by the cytochrome P450 enzyme CYP2D6, although codeine also has some (low) affinity for the μ-opioid receptor displayed in the central nervous system (CNS) and at peripheral tissues, like the gastrointestinal tract [2]. In the context of analgesic action, codeine can be considered as a prodrug. Only around 10% of codeine is converted to morphine. Other metabolic enzymes (CYP3A4, UDP-glucuronyltransferase) catalyse the conversion of codeine to other mostly inactive metabolites norcodeine (10–15%) and codeine-6-glucuronide (50–70%). Different rates of metabolism correlate with genotypes of the CYP2D6 [3]. Poor metabolizers, with one or two non-functional alleles are presented in 7–10% of the white population and may have decreased metabolism of codeine to morphine, and lower possibility for the analgesic effect in comparison to normal (extensive metabolizers). On the contrary, ultrarapid metabolism is considered to occur in 1–7% of the white population, whereas the incidence is 5–10% and 3% for Southern and Northern Europeans, respectively. As a result, in patients with more than two copies of the CYP2D6 functional allele, there is increased formation of morphine and a higher potential for experiencing adverse effects (AEs), such as sleepiness, confusion, and shallow breathing, even at recommended doses of codeine. Because of the unpredictable metabolism rate, codeine use as an analgesic drug is often replaced by other opioids, although its combination with non-opioid analgesic drugs is still largely available and used for pain treatment [4,5,6,7,8].

It has been found repeatedly that a combination of different analgesic drugs at fixed doses, rather than their single use, leads to a faster and better acute pain relief. The main purpose of such combination is the synergistic analgesic effect due to the multimodal approach to pain processing, alongside the better safety profile with no increase of the adverse effect incidence due to the initial lower doses of individual analgesics [9]. For example, the combination of non-opioid analgesic/antipyretic drugs, like paracetamol, ibuprofen, or acetylsalicylic acid with codeine was found to be rational since these substances have different mechanisms of action on pain with greater analgesic potential being possibly achieved, without reaching drugs individual toxic limits [10,11,12].

It is worth mentioning that doses of codeine in combinations with other drugs vary significantly, from 8 up to 60 mg, where a vast majority of studies investigated the effects of higher dose codeine combinations (codeine doses ≥ 30 mg).

A recent systematic review and meta-analysis by Abdel Shaheed et al. of ten randomized clinical trials investigated efficacy and safety of combination analgesic products with codeine in doses up to 30 mg and found low to moderate level of evidence for relief of acute pain. The authors found limited data about adverse effects outcomes [13].

At adult standard daily dose (30–60 mg every 4 h orally up to a maximum of 240 mg daily) codeine was found to cause no euphoria or respiratory depression. Also, despite the many speculations, existing proofs from clinical practice show it to be rarely addictive if applied as recommended [10, 14].

In this systematic review, using a comprehensive literature search strategy, we evaluated efficacy and safety of the low-dose codeine in combinations with other analgesics, to elaborate their efficacy and safety in treating acute pain. In contrast to a recent systematic review and meta-analysis [13] which evaluated the same ten studies for efficacy and safety and included single but also the multiple combination dosing regimens, here we evaluated just single-dose studies when assessing the efficacy of low-codeine combination medicinal products. Furthermore, here we focused on codeine safety in general and have included both, codeine in doses ≤ 30 mg and above, alone or in combination with other analgesics after single and multiple dosing regimens. Moreover, in addition to the scientific literature, the available individual safety reports data as retrieved from the European Medicines Agency’s (EMA) service—EudraVigilance were reviewed and the topic of substance use disorder is specially addressed.

Methods

General Search Strategy

A bibliographic database MEDLINE was searched according to the predetermined keywords (codeine, analgesia, pain, efficacy, safety, adverse event, side effect, addiction, dependence, overdose, misuse, abuse) and criteria (randomized clinical trial/study and range from inception to end of January 2019).

Search strategy was made concise enough to make sure that the exact data on efficacy and safety, along with potential for codeine use disorders is found, while remaining wide enough to include and extract the potential valuable data which could remain hidden if searching just for the codeine combination. Nevertheless, for the efficacy part, only placebo-controlled and combination studies were included in the final review.

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Study Selection

Only English language studies were included in this review. Additional filters combining human species and studies published up to January 31, 2019 were taken into consideration for obtaining relevant literature findings. Following initial screening of the titles and abstracts found for codeine, two reviewers set the keywords and criteria in place for efficacy and safety studies on codeine. One of the exclusion criteria was paediatric population due to recommended restrictions on the use of codeine for cough and cold in children. Based on the abstracts, initial judgment call was made on the potentially valuable studies. After retrieving the full texts, final decision was made on to which studies shall be included in the review. Efficacy and safety differed in final decision on importance of the found studies.

Efficacy Study Search and Selection

Since codeine’s efficacy in combination was proven time and again, especially for higher doses (> 30 mg), the main focus was to find the randomized, placebo-controlled studies which included codeine in lower doses (≤ 30 mg) in combination with another non-opioid analgesic substance. Only single dose studies were deemed acceptable. Despite the wider spectrum of codeine use, only studies focusing on analgesia were searched for (regardless of the exact indication). The selection was not limited to the duration of treatment or to the analgesic effect duration. Also, different doses of the substances in the codeine combinations were not a restriction factor.

Safety Study Search and Selection

For the purpose of safety evaluation, randomized controlled clinical studies involving medicines containing codeine either alone or in combinations, irrespective of doses, were taken into consideration. Both single and multiple dose studies, where codeine-treated subjects received at least one dose of codeine (ranging from 15 to 240 mg daily dose), for any pain condition were reviewed in order to meet the eligibility criteria. The safety profile of codeine was additionally determined involving keywords such as dependence, addiction, misuse, abuse and overdose throughout MEDLINE and EudraVigilance.

The summary on search strategy can be seen on Fig. 1.

Fig. 1
figure 1

Search strategy summary for efficacy and safety as per the predetermined inclusion and exclusion criteria

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Data Extraction and Quality Assessment

Outcome data of the final studies were extracted by two reviewers independently from each other, and were checked by the third reviewer. Recommendations from the Cochrane Handbook were applied when and where applicable.

The quality of reports of randomised controlled trials was measured using a scale indexed on PEDro (provided as supplementary material), the Physiotherapy Evidence Database (https://www.pedro.org.au/).

Results

Overview of Efficacy

Efficacy of low-dose codeine combination medicinal products was analysed through review of 16 placebo-controlled studies which involved 3378 subjects. Most of the studies were focused on codeine combination efficacy regarding surgery pain with most of them relating to the dental surgery pain (9 out of the total 16 studies) [15,16,17,18,19,20,21,22,23]; two were focused on tension headache [20, 24]; one on acute migraine attack [25]; one on post-episiotomy pain [26]; one on post-orthopaedic surgery pain [27]; one on post-photorefractive keratectomy pain [28]; and one on post-operative pain [29].

Medicinal products as found in the aforementioned studies contained the following 9 substances alongside codeine: paracetamol—nine studies [10, 16,17,18, 20, 25, 27,28,29]; acetylsalicylic acid—seven studies [15, 17,18,19, 22,23,24,25]; and ibuprofen—six studies [16, 19, 22, 23 26, 27]; followed by butalbital—three studies [16, 17, 24]; caffeine—three studies [16, 17, 24]; zomepirac—one study [24]; meclofenam—one study [21]; pentazocine—one study [29]; and propoxyphene napsylate—one study [29].

The lowest and highest doses of the most commonly used substances mentioned above were as follows: for paracetamol—300 mg and 650 mg; for acetylsalicylic acid—325 mg and 1000 mg; and for ibuprofen—400 mg and 800 mg.

None of the studies were focused on the long-term effects of codeine combination use, with the analgesic efficacy period being evaluated for all of them: 2 h was the shortest time noted [25], while 72 h being the longest time observed following single doses of combination products [28].

Twelve studies based on statistically significant results provided the final conclusion that low-dose codeine combinations are more efficient in relieving pain compared to placebo [10, 15, 17,18,19,20,21, 24,25,26, 28, 29]. Complete or almost complete pain relief was noted after: 0.5 h [24]; 1 h [15, 26, 28, 29], 2 h [25], 5 h [19], 6 h [17, 18, 20, 21], and 12-24 h [10]. Cooper and Beaver [15] discussed the minor role of codeine in analgesia, while concluding that the statistically significant efficacy of the combination is due to acetylsalicylic acid.

In contrast, two studies found codeine in combinations to be effective, but less than the comparator [16, 27]. Daniels et al. [16] compared the efficacy of paracetamol and ibuprofen combinations (ibuprofen 200 mg + paracetamol 500 mg; ibuprofen 200 mg + codeine 12.8 mg; paracetamol 500 mg + codeine 15 mg) with placebo. They found that even though low-dose codeine combinations were statistically significantly superior to placebo, ibuprofen-paracetamol combinations were more effective in pain management. Heidrich et al. [27] compared the single dose ibuprofen 400 mg with a combination of paracetamol 300 mg and codeine 30 mg. They found the single dose of ibuprofen to be more effective in pain reduction than the combination containing codeine in terms of sensory descriptors of pain. However, combination with codeine was more effective when regarding the affective descriptors of pain.

Two studies found low-dose codeine in combination to be ineffective, or modestly effective in pain treatment [22, 23]. Giles et al. [22] argued in their study the efficacy of low-dose codeine, concluding that 15 mg codeine, alone or in combination, has little to none analgesic efficacy. A dose of 15 mg was discussed to be a subtherapeutic dose with questionable possibility to show the additive effect in combination. Squires et al. [23] found no statistically significant difference between 30 mg codeine (in combination with 375 mg acetylsalicylic acid and 30 mg caffeine) and placebo in their study.

There are four studies which found low-dose codeine in combination to be effective, but less than the comparator [16, 21, 25, 27]. This potentially suggests that low-dose codeine combinations are more efficient when compared to placebo, but not when compared to other non-opioid agents.

Most of the studies which were included are from more than 30 years ago, with the oldest study found dated 1976. Conclusions from four newer studies (time period from 2011–2017) are in line with conclusions from the older ones—stating that low-dose codeine combination is more efficient in pain management when compared to placebo [10, 16, 20, 28]. Still, one of those studies found that low-dose codeine combination is as effective as the comparator [20], while one study found that such combination is less efficient than the comparator [16].

The characteristics and conclusions of the included efficacy studies are available in the Table 1.

Table 1 Characteristic and conclusions of the included efficacy studies
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Overview of Safety

Analgesics containing codeine are in general well-tolerated and usually exhibit favourable safety profile with most AEs classified as mild to moderate in severity if used for short period of time and in recommended doses. Based on the literature data discussed further in the text, the incidence of treatment discontinuation due to severe AEs is low and comparable to other treatment options for pain management.

Most of the analysed studies for safety overview included combination of non-steroidal antiinflammatory drugs (NSAIDs) with codeine in higher single dose (> 30 mg).

The overall safety of codeine alone or in combinations was assessed through 20 randomized clinical trials where codeine-treated subjects received at least one dose of codeine (ranging from 30 to 240 mg daily dose). The most represented dose within the studies was 60 mg single dose and was used in 75% of all evaluated clinical trials. Safety profiles of study medications were determined in adult patients by self-reporting of undesirable effects, including suggestive questioning regarding adverse symptoms, dependently on a study design.

Most of the performed single and multiple dose studies included codeine in combinations with paracetamol (65%), acetylsalicylic acid (25%) and ibuprofen (15%) usually for acute pain management including pre- and post-operative analgesia, headache and low-back pain. Only 3 from total of 20 evaluated studies (15%) were dealing with codeine containing analgesics being administered for up to 10 days, and these were the studies regarding chronic cancer pain [30, 31], along with outpatient breast surgery study [32]. Comparators that were used throughout the studies were standard pain killers such as paracetamol, nefopam, NSAIDs (ibuprofen, acetylsalicylic acid, ketorolac, flurbiprofen, etoricoxib, ketoprofen, piroxicam, and naproxen), opioids (tramadol) and placebo.

The list of all of the studies included in the safety analysis is provided in Table 2.

Table 2 Studies included in the safety analysis with number of patients from randomized clinical trials reporting adverse effects
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The most commonly reported AEs, regardless of study drug-relatedness, were: nausea, gastrointestinal pain, constipation, dyspepsia, vomiting, dizziness, tiredness, headache, photophobia, somnolence, dry mouth, euphoria, and faintness. The vast majority of them were mild or moderate in severity. There was no observed difference regarding the incidence of undesirable effects within the treatment groups, irrespective of acute vs. chronic pain treatment. Incidence of AEs reporting was shown to be consistent, regardless of the patient’s age, race and gender. However, study from Sagne et al. [35] indicates that AEs are more frequently experienced by women taking codeine containing pain killers and that the frequency of unwanted effects is probably weight-dependent.

Discontinuation due to AEs in both treatment and comparator group was observed in 10 from total of 20 clinical trials (50%) and was more attributed to the treatment group when comparing with the comparator group (10% vs. 3%). It is worth mentioning that majority of the serious AEs were due to toxicity of the other drug in combination product, not to codeine (ibuprofen, acetylsalicylic acid, paracetamol).

In general, the safety profile of codeine containing analgesics in doses of 30 mg and higher has been well characterised combining the results from clinical studies and extensive post-marketing surveillance. Most of the reported AEs were transient and mild to moderate in severity. There were no deaths nor serious, drug-related AEs observed following treatment with codeine.

Codeine Use Disorders

Codeine, acting as opioid receptor agonist, is a substance with a well-known risk for substance use disorder (mild, moderate or severe) due to its conversion to morphine, usually when used at higher than recommended doses for chronic pain treatment. Besides dose and duration of codeine use, a patient psychosocial characteristics (substance use disorder, previous experience with drugs, mental illnesses, etc.) are relevant for the risk of codeine use disorder. Although the liability for substance use disorder is lower than with stronger opioids, neuro-adaption and the development of such disorder may appear following inappropriate use of codeine. The misuse of codeine is considered in case of taking higher doses and/or for longer period than advisable. The potential for codeine use disorder cannot be excluded when used for recreational purposes and in excessive doses [1, 46].

Due to the fact that codeine is the very often used either alone or in combo-preparation for pain relief, there is a growing concern regarding both intentional and unintentional misuse of codeine-containing products. There are available reports claiming both, low potential for substance use disorder and common issues in relation with addictive-related disorders linked to codeine use. Following search strategy within this systematic review, there were no randomised controlled clinical studies related to codeine use disorder found. The prevalence of codeine use disorder is not likely to be determined as most of the available evidence is addressed within case study reports. Moreover, there is limitation regarding data for doses < 30 mg [1, 7, 46, 47].

Consumption of higher doses was evident in Canadian survey which involved 339 subjects who had used codeine for 3 days/week for at least 6 months and where was found that 37% of subjects who have used approximately 180 mg per day have met DSM-IV criteria for dependence [48]. Another big survey involving total of 800 subjects compared characteristics of dependent vs. non-dependent codeine users. Similar to findings from the study from Sproule et al. [49], most of the dependent patients reported family history of substance use disorders and long-term treatment for chronic pain.

Following review of EudraVigilance database, a total of 20 ICSRs (Individual Case Safety Reports) reporting dependence as a reaction were identified with codeine as a suspect drug (as a single substance, not in combination) for the time period since the January 2009 up until January 2019, for the European region. Additionally, there were 3 cases reporting medication overuse headache, while withdrawal syndrome was recorded in 25 ICSRs where codeine was defined as a suspect drug [50].

For medicinal product containing codeine phosphate sesquihydrate or hemihydrate in dose of 10 mg and in combination with paracetamol, propyphenazone and caffeine for acute pain treatment, a total of 66 ICSRs were reported for the Republic of Croatia (as found in EudraVigilance). A substance use disorder was recorded in 4 ICSRs and in most of the cases there were missing information related to other possible suspect drugs [50]. It is worth mentioning that during this 10 year period, in total, 29,520,348 packages of such combined products with low-dose codeine phosphate were sold in the territory of Croatia [51].

Discussion

Acute pain is a common condition which needs adequate therapy. Non-steroidal anti-inflammatory drugs, along with paracetamol and acetylsalicylic acid are the first line in combating the pain of low to moderate severity. Additionally, concomitant use of drugs from different classes has proved to be rational. Codeine, as a weak opioid agonist is a common ingredient of combination analgesic drugs. However, due to its opioid-like features, the codeine-containing products are often tagged with an increased risk of AEs, and with a risk of substance use disorder development. It should be noted that a vast majority of published studies regarding codeine combinations are related to the higher doses of codeine (mostly for doses ≥ 30 mg) with non-opiate analgesic, leaving a very large gap of evidence for the codeine doses below 30 mg, which are often available as over-the-counter products.

Therefore, with this systematic review, we wanted to evaluate available data related to low-dose codeine efficacy and safety along with the potential for codeine substance use disorder using a comprehensive search strategy. Efficacy and safety differed in final decision on importance of the founded studies, however with limitations of only English studies and adult population that were taken into consideration. In this systematic review, efficacy of low-dose codeine (≤ 30 mg) combination medicinal products was analysed by reviewing the 16 placebo-controlled, single-dose studies which involved 3378 subjects suffering from different types of acute pain. Out of 16 studies, 12 of them were based on statistically significant results leading to the final conclusion that low-dose codeine combinations are more efficient in relieving pain than the assigned comparator (as shown and referenced in Table 1). Four studies out of 16 found codeine in combinations to be either less effective than the comparator (two studies) or to be ineffective altogether in pain treatment (also two studies).

Similar findings in terms of efficacy for low-dose codeine combinations (15–30 mg) have been presented in recently published systematic review and meta-analysis which included 10 randomized placebo controlled clinical trials. For the purpose of codeine safety analysis, and in contrast to Shaheed et al. [13], we have extended our research and included respective data from EudraVigilance database along with available data from RTC, regardless of the codeine doses.

This review assessed the overall safety of codeine, alone or in combinations, by reviewing the 20 randomized clinical trials (as shown and referenced in Table 2). These trials included codeine-treated subjects that received at least one dose of codeine, ranging from 30 to 240 mg daily dose (with 60 mg single dose being the most represented one). Codeine containing analgesics have shown good tolerability with no statistically significant differences in adverse reactions reporting among the treatment and the comparator group (Table 2) It was also demonstrated that the most AEs are in relationship with higher dose combinations (30 or 60 mg of codeine per tablet).

In general, the safety profile of codeine containing analgesics in doses of 30 mg and higher has been well characterised combining the results from clinical studies and extensive post-marketing surveillance. When used as prescribed, for short periods of time and in recommended doses (up to 240 mg daily), most of the AEs are classified as mild to moderate in severity.

The most common challenge faced with codeine use is its well-known potential for substance use disorder. This is attributed to its conversion to morphine, usually when used at higher doses than advised and for longer periods of time (e.g. for chronic pain treatment). Although observed substance use disorder is lower than with stronger opioids, the development of such disorder may appear following the inappropriate use, usually higher than recommended daily doses either recreationally or continuously for chronic pain treatment in vulnerable patient population [1, 46].

Currently available reports can be found which claim both, low potential for substance use disorder (mild, moderate, severe) and common issues in relation with addictive-related disorders linked to codeine use. Following search strategy within this systematic review, no randomised controlled clinical studies related to codeine use disorders were found. The prevalence of codeine use disorder is not likely to be determined as most of the available evidence is addressed within case study reports. Moreover, there is limitation regarding data for doses < 30 mg. Only findings that were found for codeine use disorder pertained to the higher doses, with no exact and statistically significant data. Most of the patients with codeine use disorder have reported family history of substance use disorders and long-term treatment for chronic pain.

Conclusion

This comprehensive systematic review has found low-dose codeine combinations to be effective and safe when applied in recommended daily doses and for short periods of time. There is no indication in the available literature which clearly links low doses of codeine (alone or in combination) to substance use disorder (low, moderate, severe) issues in non-dependent subjects. In fact, we have found low-dose codeine combinations to be safe, with most of the adverse reactions reported as mild to moderate in severity. Publicly accessible data from European Medicines Agency also show a very small number of codeine use disorder adverse reactions as reported. However, to finally eliminate issues related to low-dose codeine in combination analgesic products, further well-designed clinical studies are warranted to provide more data relevant for efficacy, safety profile, and risk for substance use disorder.