Diamorphine Hydrochloride
A white or almost white crystalline powder, odourless when freshly prepared but develops an odour characteristic of acetic acid on storage. Freely soluble in water and in chloroform; soluble in alcohol; practically insoluble in ether. Protect from light.
Physicochemical Characteristics
Incompatibility.
Diamorphine hydrochloride is incompatible with mineral acids and alkalis and with chlorocresol.
The BNF notes that cyclizine may precipitate from mixtures with diamorphine hydrochloride at concentrations of cyclizine greater than 10 mg/mL, or in the presence of sodium chloride, or as the concentration of diamorphine relative to cyclizine increases; mixtures of diamorphine and cyclizine are also liable to precipitate after 24 hours.
It also considers that mixtures of diamorphine and haloperidol are liable to precipitate after 24 hours if the haloperidol concentration is above 2 mg/mL. Under some conditions mixtures of metoclopramide and diamorphine may become discoloured and should be discarded.
Stability.
Diamorphine is relatively unstable in aqueous solution and is hydrolysed to 6-O-monoacetylmorphine and then morphine to a significant extent at room temperature; 3-O-mono-acetylmorphine is only occasionally detected. The rate of decomposition is at a minimum at about pH 4.
In a study of the stability of aqueous solutions of diamorphine in chloroform water it was concluded that such solutions should be used within 3 weeks of preparation when stored at room temperature. Another study noted that the degradation products of diamorphine were not devoid of analgesic activity. Using a more sensitive analytical method it was reported that although the pH range of maximum stability of diamorphine in aqueous solution was 3.8 to 4.4, the addition of buffers reduced stability. Simple unbuffered chloroform water gave maximum stability, the shelf-life of such a solution being 4 weeks at room temperature.
The BP 2005 recommends that solutions for injection be prepared immediately before use by dissolving Diamorphine Hydrochloride for Injection in Water for Injections. This may pose a problem with solutions for subcutaneous infusion when concentrated solutions may remain in infusion pump reservoirs for some time. Investigation of 9 concentrations of diamorphine stored at 4 different temperatures for 8 weeks revealed instability under conditions of concentration, time, and temperature prevalent during subcutaneous infusion. Degradation of diamorphine occurred at all concentrations (0.98 to 250 mg/mL) at temperatures of 4 degrees and above; the effect of temperature was significant at 21 degrees and 37 degrees. The percentage fall in diamorphine concentration was directly related to initial concentration and was accompanied by a corresponding increase in 6-O-monoacetylmorphine and, to a lesser extent, morphine; other possible breakdown products such as 3-O-monoacetylmorphine were not present in detectable quantities. Diamorphine degradation was associated with a fall in pH and the development of a strong acetic acid-like odour. Precipitation and a white turbidity was seen in solutions of 15.6 mg/mL and above after incubation for 2 weeks at 21 degrees and 37 degrees. It has been noted that solutions for infusion are generally freshly prepared and used within 24 hours, but that signs of precipitation should be watched for, especially when using longer-term infusions and high concentrations of diamorphine.
In another stability study diamorphine hydrochloride in concentrations of both 1 and 20 mg/mL in sodium chloride 0.9% was stable for a minimum of 15 days at room temperature (23 degrees to 25 degrees) and 4 degrees when stored in a PVC container. In one type of disposable infusion device (Infusor) similar solutions were stable for 15 days even at 31 degrees. In another infusion device (Intermate 200) diamorphine was stable for a minimum of 15 days at both concentrations and all temperatures except for the 1 mg/mL solution kept at 31 degrees when stability was only maintained for a minimum of 2 days. When stored in glass syringes both strengths of diamorphine hydrochloride were stable for 15 days at 4 degrees and at room temperature the 1 mg/mL solution was stable for a minimum of 7 days and the 20 mg/mL solution was stable for a minimum of 12 days. There were no substantial changes in physical appearance or pH.
Dependence and Withdrawal
As for Opioid Analgesics, . Diamorphine is subject to abuse (see under Adverse Effects, Treatment, and Precautions.
Diamorphine is used for substitution therapy in the management of opioid dependence (see under Uses and Administration.
Adverse Effects, Treatment, and Precautions
As for Opioid Analgesics in general.
Pulmonary oedema after overdosage is a common cause of fatalities among diamorphine addicts. Nausea and hypotension are claimed to be less common than with morphine.
There are many reports of adverse effects associated with the abuse of diamorphine, usually obtained illicitly in an adulterated form.
Abuse.
Most of the reports of adverse effects with diamorphine involve its abuse. In addition to the central effects, there are effects caused by the administration methods and by the adulterants. Thus in many instances it is difficult to identify the factor causing the toxicity. Most body systems are involved including the immune system, kidneys, liver, respiratory system, and the nervous system.
Other aspects of the illicit use of diamorphine include fatal overdose and smuggling by swallowing packages of drug or other methods of internal bodily concealment.
Administration.
Although generally free from complications, sterile abscess formation was reported in 2 patients with advanced cancer receiving diamorphine by continuous subcutaneous infusions. Acute dysphoric reactions have been reported after the use of epidural diamorphine.
Breast feeding.
The American Academy of Pediatrics has stated that, when used as a drug of abuse by breast-feeding mothers, diamorphine has caused adverse effects in the infant, notably tremors, restlessness, vomiting, and poor feeding.
See also under Opioid Dependence in Uses and Administration.
Phaeochromocytoma.
Diamorphine can liberate endogenous histamine which may in turn stimulate release of catecholamines. Its use provoked hypertension and tachycardia in a patient with phaeochromocytoma.
Pregnancy and the neonate.
Some references to diamorphine dependence in pregnant women and the effects on the fetus and neonate.
Interactions
For interactions associated with opioid analgesics, see below.
As serious and sometimes fatal reactions have followed use of pethidine in patients receiving MAOIs (including moclobemide), pethidine and related drugs are contra-indicated in patients taking MAOIs or within 14 days of stopping such treatment; other opioid analgesics should be avoided or given with extreme caution. Life-threatening reactions have also been reported when selegiline, a selective inhibitor of monoamine oxidase type B, has been given with pethidine. The depressant effects of opioid analgesics are enhanced by other CNS depressants such as alcohol, anaesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Cyclizine may counteract the haemodynamic benefits of opioids. Cimetidine inhibits the metabolism of some opioids, especially pethidine.
The actions of opioids may in turn affect the activities of other drugs. For instance, their gastrointestinal effects may delay absorption as with mexiletine or may be counteractive as with cisapride, metoclopramide, or domperidone. Opioid premedicants such as papaveretum have been reported to reduce serum concentrations of ciprofloxacin.
Pharmacokinetics
Diamorphine hydrochloride is well absorbed from the gastrointestinal tract and after subcutaneous or intramuscular injection. On injection it is rapidly converted to the active metabolite 6-O-monoacetylmorphine (6-acetylmorphine) in the blood and then to morphine. Oral doses are subject to extensive first-pass metabolism to morphine; neither diamorphine nor 6-acetylmorphine have been detected in the blood after giving diamorphine by this route. Both diamorphine and 6-acetylmorphine readily cross the blood-brain barrier. Morphine glucuronides are the main excretion products in the urine. A small amount is excreted in the faeces.
Reviews and studies of the pharmacokinetics of diamorphine.
Administration.
Diamorphine is much more lipid-soluble and has a more rapid onset and shorter duration of action than morphine. Although deacetylation to morphine occurs rapidly in the blood it occurs only slowly in the CSF following intraspinal injection of diamorphine. After intrathecal injection diamorphine was removed from the CSF much more rapidly than morphine. Peak plasma concentrations of morphine following epidural diamorphine injection were significantly higher and were achieved significantly faster than after epidural injection of morphine.
Children.
Loading doses of either 50 micrograms/kg or 200 micrograms/kg of diamorphine were given as an infusion over 30 minutes to 19 ventilated neonates followed by a continuous infusion of 15 micrograms/kg per hour, and the pharmacokinetics of the products of diamorphine metabolism (morphine, morphine-6-glucuronide, and morphine-3-glucuronide) studied. Although the overall elimination of morphine was reduced compared with adults, the relative contributions of the various metabolic routes of morphine remained similar between neonates and adults. Data from this study did not indicate any advantage for the higher loading dose (see also under Uses and Administration).
Uses and Administration
Diamorphine hydrochloride is an acetylated morphine derivative and is a more potent opioid analgesic than morphine. Diamorphine is used for the relief of severe pain especially in palliative care. It is also used similarly to morphine for the relief of dyspnoea due to pulmonary oedema resulting from left ventricular failure. Diamorphine has a powerful cough suppressant effect and has been given as Diamorphine Linctus (BPC 1973) to control cough associated with terminal lung cancer although morphine is now preferred.
In the treatment of acute pain standard doses of diamorphine hydrochloride by subcutaneous or intramuscular injection are 5 to 10 mg every 4 hours. Doses equivalent to one-quarter to one-half of the corresponding intramuscular dose may be given by slow intravenous injection.
For the pain of myocardial infarction diamorphine hydrochloride is given in doses of 5 mg by slow intravenous injection at a rate of 1 mg/minute with a further dose of 2.5 to 5 mg if required; doses may be reduced by one-half for elderly or frail patients. Doses of 2.5 to 5 mg may be given intravenously at the same rate for acute pulmonary oedema.
For chronic pain 5 to 10 mg may be given by subcutaneous or intramuscular injection every 4 hours; the dose may be increased according to needs. Similar doses may be given by mouth, although it is converted to morphine by first-pass metabolism. Diamorphine hydrochloride may also be given by continuous subcutaneous infusion or intraspinally.
For dosage in children see below.
Action.
Because of its abuse potential, supply of diamorphine is carefully controlled and in many countries it is not available for clinical use; morphine can provide equivalent analgesia by dose adjustment. There has been much debate regarding the relative merits of analgesia with diamorphine or morphine. Many now regard oral morphine to be the opioid analgesic of choice although diamorphine hydrochloride may be preferred for injection because it is more soluble in water thus allowing the use of smaller dose volumes. Diamorphine hydrochloride may also be preferred to morphine salts for intraspinal use because it is more lipid-soluble.
As a guide to relative potency diamorphine hydrochloride 5 mg intramuscularly is approximately equivalent to 10 mg by mouth which in turn is approximately equivalent to morphine sulfate 15 mg by mouth.
Administration in children.
In the treatment of acute or chronic pain in children, the BNFC suggests the following doses:
by continuous intravenous infusion
neonates with spontaneous respiration may be given 2.5 to 7 micrograms/kg per hour
ventilated neonates may be given 50 micrograms/kg initially by intravenous injection over 30 minutes followed by 15 micrograms/kg per hour by continuous intravenous infusion
1 month to 12 years of age, 12.5 to 25 micrograms/kg per hour
by intravenous injection
1 to 3 months of age, 20 micrograms/kg every 6 hours if necessary
3 to 6 months of age, 25 to 50 micrograms/kg every 6 hours if necessary
6 to 12 months of age, 75 micrograms/kg every 4 hours if necessary
1 to 12 years of age, 75 to 100 micrograms/kg every 4 hours if necessary
by mouth
1 month to 12 years of age, 100 to 200 micrograms/kg (maximum of 10 mg) every 4 hours if necessary
In a study of the effects of diamorphine in 34 premature infants (gestational age 26 to 40 weeks), a loading dose of 50 micrograms/kg given as an intravenous infusion over 30 minutes followed by a continuous infusion at a rate of 15 micrograms/kg per hour was considered to be safe and resulted in plasma concentrations of morphine comparable with those that usually produce adequate analgesia in children and adults; the duration of the infusion ranged from 14 to 149 hours. Small but significant reductions in heart rate and mean blood pressure were noted but these were not associated with any clinical deterioration. The fall in respiration rate reflected the desired intention to encourage synchronisation of the infants' breathing with the ventilator. The authors concluded that intravenous diamorphine could be given safely to neonates and would provide adequate analgesia. A later study indicated that the use of a 200 micrograms/kg loading dose conferred no benefit over a 50 micrograms/kg dose and might produce undesirable physiological effects. In a comparative study with morphine (200 micrograms/kg loading dose over 2 hours, followed by maintenance infusion of 25 micrograms/kg per hour) in ventilated preterm neonates requiring sedation, diamorphine (120 micrograms/kg over 2 hours and then 15 micrograms/kg per hour) was as effective as morphine in producing sedation and also had a faster onset of action. The small but significant drop in blood pressure noted during morphine infusions was not seen with diamorphine infusions. Continuous intravenous infusions of 7 micrograms/kg per hour have been used in neonates not requiring ventilation.
The subcutaneous route appeared to be as effective and safe as the intravenous route for infusions in children for postoperative pain relief after elective abdominal surgery. The dose of diamorphine used in both groups of children was 1 mg/kg given at a rate of 20 micrograms/kg per hour.
Intranasal diamorphine has been investigated in adults and children, and appears to be effective and well tolerated; because it does not require a needle it may offer particular advantages in children. Guidelines for analgesia in children in Accident and Emergency departments in the UK recommend the use of intranasal diamorphine for severe pain such as that associated with large burns, long bone dislocation, appendicitis, or sickle cell crisis. A suggested dose to be instilled into one nostril is 100 micrograms/kg given in 0.2 mL of sterile water.
Opioid dependence.
Many opiate misusers have expressed a preference for withdrawal using diamorphine rather than methadone. In a comparative study stabilisation was achieved using either diamorphine or methadone 1 mg/mL oral solutions; patients could not identify which they had been given. Whenever signs of physical withdrawal were observed 10 mL of either solution was given and the total amount over the first 24 hours taken as the patient's daily requirement. The mean dose of diamorphine required for stabilisation was 55 mg compared with 36 mg for methadone. Some centres have given diamorphine in the form of reefers. Diamorphine has also been prescribed in combination with methadone in the management of addicts.
Breast feeding has been used to treat diamorphine dependence in the offspring of dependent mothers but this is no longer considered to be the best method and some authorities recommend that breast feeding should be stopped.
Pain.
Acute Pain.
Rapid pain relief may be obtained with the intravenous injection of diamorphine. Other routes include the intraspinal route for which diamorphine is well suited because of its lipid solubility and pharmacokinetics. Epidural doses of diamorphine have ranged from 0.5 to 10 mg. Analgesia was significantly more prolonged and more intense after epidural rather than intramuscular injection of diamorphine 5 mg in women who had had caesarean section; itching was reported by 50% of patients undergoing epidural analgesia. Epidural diamorphine alone or with bupivacaine has been used for analgesia during labour; addition of adrenaline appeared to improve the quality and duration of analgesia with diamorphine. In another study addition of diamorphine to bupivacaine produced a high incidence of pruritus and drowsiness.
Continuous epidural infusion of diamorphine 0.5 mg/hour in 0.125% bupivacaine provided postoperative analgesia superior to that with either drug alone in patients undergoing major abdominal gynaecological surgery. A similar infusion produced analgesia superior to that with either epidural bolus injection or patient-controlled intravenous diamorphine in patients undergoing total abdominal hysterectomy. However, more patients receiving the continuous epidural infusion were hypoxaemic than in the other 2 groups.
Diamorphine has also been given intrathecally for postoperative analgesia and should be effective at lower doses than with the epidural route because of greater CSF concentrations. Diamorphine 0.25 or 0.5 mg given intrathecally with bupivacaine spinal anaesthesia both provided greater postoperative analgesia than bupivacaine alone, but the incidence of adverse effects, especially nausea, vomiting, and urinary retention, was still high with either dose and routine use of this technique was not recommended. Intrathecal diamorphine with bupivacaine has also been used for analgesia during labour.
Diamorphine has been extensively used by cardiologists in the UK for the management of pain in acute left ventricular failure, unstable angina, and myocardial infarction. It has been theorised that diamorphine may offer benefits over morphine because its stimulatory effects at opioid ? receptors on the myocardium may reduce the extent of myocardial damage. Evidence to support this theory is, however, lacking.
Chronic pain.
Patients with chronic opioid-sensitive pain are often treated with diamorphine given by continuous subcutaneous infusion using a small battery-operated syringe driver. The following technique has been described. Diamorphine hydrochloride 1 g could be dissolved in 1.6 mL of water to give a solution with a volume of 2.4 mL (415 mg/mL), but the maximum suggested concentration was 250 mg/mL. If the analgesic requirement was not known the following protocol was recommended:
Start injections every 4 hours of 2.5 or 5 mg diamorphine, or, if the patient has already been taking opioids, a dose that is equivalent to the last dose
If this is unsatisfactory increase this dose in 50% increments until the patient reports even a little pain relief
Calculate the 24-hour requirement by multiplying by six, and start the infusion at this level
Increase the 24-hour dosage in the pump by 50% increments until the pain is controlled. Note that requirements may vary from less than 20 mg to more than 5 g per 24 hours.
When starting an infusion it is important not to allow any breakthrough pain. This may be achieved either by starting the infusion more than 2 hours before the previous oral dose wears off or by giving a loading dose injection of the 4-hourly requirement.
Although generally free from complications, sterile abscess formation was reported in 2 patients with advanced cancer receiving diamorphine by continuous subcutaneous infusions.
The intraventricular route was used successfully in 2 patients with intractable cancer pain.