Hydromorphone

Potent Opioid Analgesic with Controlled-Substance Status for Severe Pain

Hydromorphone is a semi-synthetic opioid analgesic and a derivative of morphine. It is approximately five to eight times more potent than morphine and belongs to the most powerful analgesics used in clinical practice. Hydromorphone is used primarily for strong to very strong chronic pain that no longer responds adequately to weaker analgesics, particularly in oncological pain management and palliative medicine.

Well-known brand names are Palladon and Jurnista (an extended-release formulation with 24-hour activity). Hydromorphone is available as capsules, extended-release tablets, injection and infusion solutions, and for epidural and intrathecal administration. Its high analgesic potency and good bioavailability make hydromorphone an important reserve agent when morphine is insufficiently effective or not tolerated.

Controlled-Substance Status

Hydromorphone is listed as a controlled substance in many countries. Every prescription requires a special controlled-substance prescription containing specific mandatory information. Physicians are subject to strict record-keeping and reporting obligations. Dispensing by pharmacies is subject to particular requirements.

Patients must not pass hydromorphone on to third parties. Illegal distribution, illegal importation or possession without a prescription constitute criminal offences under applicable narcotics legislation.

Mechanism of Action

Hydromorphone is a selective and highly potent agonist at mu opioid receptors (MOR). Binding to MOR activates Gi proteins that inhibit neuronal excitability via several signalling pathways: potassium channels are opened (hyperpolarisation), calcium channels are closed and adenylate cyclase is inhibited. In the nociceptive system this leads to reduced release of pain mediators (substance P, glutamate) and inhibition of nociceptive signal transmission in the spinal cord and supraspinal pain-processing centres.

Hydromorphone has greater lipophilicity than morphine, resulting in a faster onset of action in the central nervous system. The active metabolite hydromorphone-6-glucuronide (H6G) contributes to a small extent to the analgesic effect but can accumulate in renal insufficiency and cause neurotoxicity. Unlike morphine, hydromorphone produces little hydromorphone-3-glucuronide (H3G) with excitatory effects, which may be advantageous in patients with morphine-induced neurotoxicity.

Indications

• Severe cancer pain: Used at WHO analgesic ladder step III when weaker opioids are insufficient
• Chronic non-malignant pain (CNMP): In exceptional cases and with strict indication when pain cannot be controlled by other means
• Postoperative pain: Intravenous or subcutaneous administration for severe postoperative pain when oral therapy is not possible
• Palliative medicine: Pain management, dyspnoea relief and sedation in the terminal phase
• Pain crisis and breakthrough pain: Fast-acting formulations for acute pain peaks in cancer patients

Dosage and Administration

Dosing of hydromorphone is individualised and depends on pain intensity, prior opioid requirements and tolerability. In opioid-naive patients, therapy begins with low doses (1 to 2 mg every 4 to 6 hours as immediate-release capsules, or 4 to 8 mg every 24 hours as an extended-release formulation). Step-wise dose titration is required.

For opioid rotation (switching from morphine to hydromorphone), an equianalgesic ratio of approximately 5:1 (morphine: hydromorphone) is used as a reference. The actual conversion dose should be individually adjusted and chosen conservatively. In renal or hepatic insufficiency, particular caution and close monitoring are required; dose interval or dose may need to be reduced.

Extended-release tablets (Jurnista) must not be broken, chewed or crushed. The integrity of the extended-release matrix is essential for safe drug release.

Side Effects

The side-effect profile of hydromorphone corresponds to that of other potent opioids. Very common (more than 10 percent) are constipation, nausea and vomiting, which should be treated prophylactically. Constipation, unlike other opioid side effects, does not diminish with tolerance development and requires ongoing concomitant laxative therapy.

Sedation, dizziness, headache, dry mouth and sweating occur commonly. Respiratory depression is the most dangerous and potentially life-threatening adverse effect, which can occur with overdose or rapid intravenous injection. The risk is substantially increased by concomitant use of other respiratory-depressant substances. Other possible effects include urinary retention, pruritus, euphoria or dysphoria, and muscle twitching at high doses or with metabolite accumulation.

With prolonged use, tolerance, physical dependence and possibly psychological dependence develop. Discontinuation must be gradual and under medical supervision to avoid withdrawal symptoms.

Drug Interactions

Centrally depressant substances such as benzodiazepines, other opioids, barbiturates, antidepressants, antipsychotics and alcohol substantially enhance the respiratory-depressant and sedating effects of hydromorphone and can cause life-threatening situations. MAO inhibitors must not be used concurrently and not within 14 days after discontinuation.

Anticholinergic substances can potentiate constipation and urinary retention. CYP3A4 inhibitors (e.g. azole antifungals, macrolide antibiotics, grapefruit juice) can increase hydromorphone plasma levels. Naloxone and naltrexone reverse the analgesic effect and can precipitate acute withdrawal in physically dependent patients.

Special Notes

Hydromorphone is contraindicated during pregnancy and breastfeeding. Neonates born to mothers who have taken hydromorphone may experience respiratory depression and neonatal opioid withdrawal syndrome. Patients with bronchial asthma, COPD, sleep apnoea, raised intracranial pressure or paralytic ileus should receive hydromorphone only with particular caution and under intensive monitoring.

Patients taking hydromorphone should not drive and should not operate machinery. Individual fitness to drive must be assessed by a physician; in some cases, with a stable dose-setting phase and sufficient experience with the dosage, limited fitness to drive may exist. Hydromorphone must be stored securely, out of reach of children and third parties.

Frequently Asked Questions

What is the difference between hydromorphone and morphine?

Hydromorphone is approximately five to eight times more potent than morphine with comparable administration. It produces less of the potentially neurotoxic metabolite H3G than morphine and may therefore represent an alternative for patients who do not tolerate morphine (e.g. due to neurotoxicity or morphine intolerance). Both are subject to controlled-substance legislation.

How dangerous is a hydromorphone overdose?

A hydromorphone overdose is a medical emergency. It leads to respiratory depression, loss of consciousness, extreme miosis (pupil constriction) and can be fatal without immediate treatment. The opioid antagonist naloxone reverses the effect and is the drug of choice in emergency management.

Can tolerance develop to hydromorphone?

Yes, with prolonged use, tolerance to many effects (analgesia, sedation, nausea) develops. The analgesic dose may need to be adjusted over time. Tolerance to constipation generally does not develop, which is why laxatives should be continued on an ongoing basis.

Why must extended-release hydromorphone not be divided?

The extended-release formulation (e.g. Jurnista) contains the active substance in a special matrix that releases it slowly over 24 hours. If the tablet is divided, broken or chewed, all of the active substance is released at once. This can cause a life-threatening overdose with severe respiratory depression.

References and Further Information

• Applicable national narcotics legislation and prescribing regulations
• Summaries of Product Characteristics for Palladon and Jurnista (current versions)
• S3 Guideline on Palliative Medicine for Patients with Non-Curable Cancer (AWMF)
• S3 Guideline on Treatment of Chronic Non-Cancer Pain (AWMF)
• WHO: Palliative Care and Pain Management Guidelines
• Federal Institute for Drugs and Medical Devices (BfArM)