Dihydrocodeine: safety concerns

Abstract

Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine, which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule - instead of a double bond between carbons 7 and 8 DHC possesses a single bond. DHC is used as an analgesic and antitussive agent and for the management of dyspnea and opioid addiction. Limited data is available on the potency of DHC to other opioids. The analgesic effect of DHC is similar to codeine and approximately twice as potent as tramadol for an oral route. In contrast to codeine and tramadol, DHC analgesia seem to be irrespective of CYP2D6 activity due to parent compound analgesic effects, multiple metabolic pathways and limited role of dihydromorphine in DHC analgesia. As the drug is commonly available appropriate titration and dosing and knowledge of its metabolism and possible adverse effects are important for safe prescription of DHC.

Keywords:

• adverse effects
• analgesia
• dihydrocodeine
• opioids
• safety

Dihydrocodeine (DHC) is a semi-synthetic analogue of codeine which was formed by the hydrogenation of the double tie in the main chain of the codeine molecule [1]. DHC compared to codeine possesses a single bond instead of a double bond between carbons 7 and 8 [2]. DHC is used as an analgesic, antitussive agent; it is also used for the treatment of opioid addiction [3]. Limited data are available on the relative potency of DHC to other opioids. In patients with postoperative pain after subcutaneous administration of 30 mg DHC analgesia was similar to that induced by 10 mg of morphine. DHC administered by the oral route possesses similar analgesic potency to codeine and it is approximately twice as potent as tramadol with suggested equianalgesic doses of controlled-release formulations DHC 60 mg and tramadol 100 mg [4].

The place of dihydrocodeine in pain management

Dihydrocodeine (DHC) may be placed at the second step of the WHO analgesic ladder as a ‘weak’ opioid. However, it clearly possesses stronger analgesic effect compared to tramadol. It may be especially useful for patients suffering from chronic pain of moderate to strong intensity, especially with concomitant cough and dyspnea. This may be very common situation in patients with advanced lung cancer [5]. Although long-acting opioid formulations are preferred for chronic pain management a recent controlled study conducted among patients with chronic non-malignant pain did not demonstrate any advantage of a controlled-release over immediate-release DHC formulations [6].

From a practical point of view prophylaxis with laxatives should be considered when starting DHC treatment as suggested by results of clinical studies conducted in patients with cancer-related and chronic non-malignant pain [4,6–8]. DHC rarely induces nausea and vomiting and in most patients the drug is well-tolerated, therefore, prophylaxis of nausea and vomiting is not routinely recommended [9].

Another advantage compared to tramadol (which displays both opioid and non-opioid components of analgesia) and codeine (which is a prodrug metabolized to morphine) is the fact that DHC analgesia probably does not depend on the CYP2D6 activity. This enzyme is responsible for DHC O-demethylation to dihydromorphine, although it is formed in small amount and its role in DHC analgesia is limited [10]. Moreover, there are other metabolic pathways of DHC through N-demethylation to norcodeine and glucuronidation to DHC-6-glucuronide, which are formed in larger amount, which further increase in case of inactive CYP2D6 enzyme (poor metabolizers) with the parent compound displaying significant analgesic effects [4]. This issue is especially important in ultrarapid metabolizers (who may experience excessive adverse effects) and poor metabolizers of CYP2D6 (who may have impaired analgesia) after codeine [10] and tramadol administration [11]. Moreover, in contrast to tramadol in case of DHC there is a less risk of an appearance of serotonin syndrome when the drug is combined with selective serotonin reuptake inhibitors or seizures when combining with tricyclic antidepressants [12].

Possible adverse effects of DHC

A medicine is only made available to the public if the clinical trials have shown that the benefits of taking the medicine outweigh the risks. Once a medicine has been licensed, information on the medicine’s effects, both intended and unintended, is continuously recorded and updated. Some side effects may be serious while others may only be a mild inconvenience. Everyone’s reaction to a medicine is different. It is difficult to predict which side effects will you have from taking a particular medicine, or whether you will have any side effects at all [13].

The use of DHC in clinical practice is associated with effective analgesic effect. However, due to the pharmacodynamic mechanism of action of DHC side effects may appear, which are mainly related to the affinity of the drug to opioid receptors. Adverse events observed in patients receiving DHC are listed below, also in relation to the frequency of their occurrence [14].

In clinical practice, the most important are those side effects that occur with considerable frequency. They can both impair the quality of analgesia on the one hand, on the other hand adversely affect the quality of life of the patient, which is not without significance, especially during long-term treatment. Frequently, following administration of DHC dry mouth, sleepiness, stomach pain, nausea and vomiting may be observed. These problems tend to occur in more than one patient out of 100 treated with DHC. Side effects such as nausea and vomiting can be alleviated or even totally eliminated by the administration of antiemetics.

However, the most common side effect that occurs in patients treated with DHC is constipation. While in the previously described side effects phenomenon of tachyphylaxis usually appears, the severity of constipation while taking DHC remains at a similar level, and may even be subject to escalation. Laxatives should be used as prophylaxis and usually they must be administered for the whole time of DHC treatment. In case laxative doses must be increased it also increases the likelihood of their adverse effects and abdominal pain.

Among other less common clinical adverse reactions hypersensitivity reactions should be mentioned that manifest in the form of angioedema, urticaria and skin rash. Therefore, it is important to collect before the use of DHC history regarding pre-existing, drug-induced side effects. DHC may also induce itching. In patients with a tendency to hypotension and in those taking antihypertensive drugs, especially diuretics and calcium channel blockers, after using the DHC hypotension may occur, which particularly in the elderly may increase the risk of falls.

Most of the opioid analgesics can decrease libido, which may be related to effects of these drugs on the release of gonadotropins. These side effects can also affect the urinary tract and may include the occurrence of renal colic and urinary retention. The latter side effect is most common in men with significant benign prostatic hyperplasia.

In elderly patients, who in addition to DHC use other drugs with sedative effects, these combinations may increase the risk of confusion, but also attention should be paid to elderly patients taking benzodiazepines with DHC which increase the risk of hallucinations. Independent risk factor for this complication is dehydration, as well as additional medication with strong central anticholinergic effects. On the other hand, side effects in the CNS include convulsions, headaches and vertigo. Patients should be informed that after DHC administration blurred vision may appear.

When adopting DHC, especially in the case of overdose, the possibility of respiratory depression should be kept in mind. In the case of a prolonged administration tolerance to analgesic effects may occur, which often forces to escalate doses of DHC, but also increase the risk of side effects. A 65-year old patient with respiratory depression was depicted who experienced chronic obstructive pulmonary disease (COPD) exacerbation. However, the patient increased on her own a dose of 120 mg of controlled-release DHC twice daily (the maximal daily dose recommended by the British National Formulary and Summary of Product Characteristics) [15] for the treatment of low back pain to a dose of 240 mg twice daily with additional dose for breakthrough pain management. Two days after DHC dose increments the patient developed hypercapnic respiratory failure that was initially attributed to COPD exacerbation but as it responded dramatically to intravenous bolus followed by a continuous infusion of naloxone it was evoked by DHC overdosage [16].

With the sudden discontinuation of DHC withdrawal symptoms can occur including feeling restless or irritable. The frequency of side effects such as difficulties in concentrating and worsening of headaches if DHC is used to treat headaches for a long time is unknown.

DHC may rarely evoke priapism. The risk of this complication is increased in patients receiving concomitant α-1 blockers, phenothiazines, trazodone and phosphodiesterase Type 5 inhibitors. In the assessment of the effectiveness of the drug in the pharmacotherapy of pain, it is extremely important to evaluate both the clinical effectiveness and the risk of side effects. A case report of an acute generalized exanthematous pustulosis caused by DHC in a 60-year old patient with psoriasis vulgaris and a heterozygous IL36RN mutation was published. This indicated on a possibility of appearance of acute skin reactions after DHC administration in patients with generalized pustular psoriasis and IL36RN mutation, which induces uncontrolled signaling of IL-36 [17].

There are reports about the possibility of inducing renal failure by the DHC. Significant risk factors for kidney failure are the age of the patient, dehydration, as well as the current administration of nephrotoxic drugs and chemotherapy that may harm the kidneys.

Park et al. depicted two patients who developed severe narcosis and acute renal failure following therapeutic DHC doses. DHC was administered orally in the following doses: a 50-year old patient with chronic renal failure received 30–60 mg every 4–6 h for 5 days (the total dose equaled 510 mg) and another 70-year old patient was treated with the dose 10 mg DHC plus 500 mg of paracetamol (Co-dydramol tablets) three times a day (the total doses were 140 mg and 5.5 g, respectively, in 5 days). In both patients naloxone increased respiratory minute volume and improved level of consciousness; moreover, a reversal of renal failure with an increased urine output and creatinine clearance during naloxone administration was observed. A possibility of DHC and its metabolites contribution to renal failure should be considered especially in patients with a history of renal impairment and in the elderly; the investigators recommend careful use of DHC in both patient populations [18].

A serious adverse event of DHC (a fall in blood pressure, loss of consciousness, myoclonic jerks, respiratory depression) was found in a 41-year old female patient with renal failure who underwent peritoneal dialysis therapy and for 4 days treated with oral DHC in a dose of 60 mg three times daily (the total dose administered was 600 mg). The symptoms disappeared after treatment with continuous naloxone infusion (the total dose was 8 mg administered within 48 h) and breathing support. An increase of blood pressure and generalized seizures were observed, which vanished after naloxone cessation. The laboratory investigations unveiled high serum DHC level (1 mg/l). The parent drug and metabolites accumulation with factors such as an increase of a drug fraction unbound with proteins, possible interactions with endogenous opioids rendered DHC toxicity [19]. There is a need to evaluate the impact of renal failure on pharmacokinetics and pharmacodynamics of DHC especially in terms of active metabolites which may accumulate.

Antidepressants and antipsychotics may display pharmacodynamic interaction with DHC by increasing sedative and depressant effects of DHC on CNS. This is also the case for benzodiazepines [20]. The interaction between DHC and benzodiazepines is associated with a summation of their adverse effects in the CNS. Patients taking concurrently opioids and benzodiazepines may experience more often excessive sedation, especially those of advanced age have an increased risk of confusion and falls. An increased risk of DHC interaction is associated with the concurrent administration of a benzodiazepine having a long plasma half-life, in particular, clorazepate and diazepam [21]. Co-administration of DHC with benzodiazepines, methadone and heroin may increase the risk of accidental, fatal overdose. DHC was attributed as a cause of 6.8% of all opioid-related deaths in the UK in the period of 1997–2007. The results suggest caution when prescribing DHC to opioid addicts for either maintenance or detoxification therapy [22]. The issue of a safe use of DHC is of great importance in the light of the use of DHC in the treatment of heroin addiction and a large availability of DHC including possiblility of obtaining from rogue online pharmacies.

Conclusions

Knowledge of the profile of adverse reactions caused by the DHC allows both reasonably choose DHC for the treatment of pain and limit its use in populations where the risk is particularly high. It is important to comply with recommended daily dose limitations (a maximal daily dose of DHC is 240 mg), starting with the lowest available doses and carefully titrate with paying attention to analgesia and possible adverse effects. This especially refers to vulnerable patient populations such as elderly patients, those with co-morbidities and organ impairment. A prophylaxis with laxatives should be prescribed and close monitoring for adverse effects should be instituted, especially during titration period.

For patients with chronic pain of moderate to severe intensity and of those with accompanying cough and dyspnea DHC is a reasonable choice unless renal failure is present. In this situation when opioids are required fentanyl, buprenorphine and methadone are better options. DHC may also be considered for patients who do not respond to tramadol regarding analgesia and/or when it induces intolerable adverse effects.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.