Opioid therapy in severe pain

Opioids have no standard dose. The effect varies tenfold between individuals, and the only way to find the right level is to give a small dose, wait until it has worked, and assess the effect before the next one is given. The serious incidents almost always arise when the principle of titration is abandoned — when a fixed dose is given without assessment, when a modified-release preparation is started in an opioid-naive patient, or when a conversion between drugs is made without reduction for incomplete cross-tolerance.

Indications

• Acute severe nociceptive pain where paracetamol and a COX inhibitor are not enough: fracture, renal colic, ischaemic pain, pancreatitis, major trauma.
• Postoperative pain.
• Cancer-related pain and pain in the palliative phase.
• Severe breathlessness in the palliative phase (at lower doses than for pain).

An opioid is rarely the right choice in nociplastic or neuropathic pain, in chronic non-cancer pain, or in headache. A failure to improve function is a reason to taper off, not to increase the dose.

Contraindications

• Ongoing respiratory depression, or untreated severe respiratory failure without the possibility of monitoring.
• Paralytic ileus and suspected obstructive ileus (an opioid can be given for the pain, but the effect on the bowel must be taken into account).
• Known allergy to the preparation — rare; itching and urticaria are usually due to histamine release, not allergy.
• Concurrent MAO inhibitor, particularly with pethidine.
• Caution: untreated sleep apnoea, a concurrent benzodiazepine or gabapentinoid, marked hypovolaemia, head injury with impaired consciousness, biliary tract disease.

There is no contraindication to analgesia in the acute abdomen. The notion that an opioid masks the diagnosis has been disproved — withholding it delays the investigation instead.

Preparation and equipment

• Working venous access and an infusion solution.
• A pulse oximeter, a blood pressure cuff, a clock. The respiratory rate is counted manually.
• Naloxone 0.4 mg/mL out and checked before the first intravenous dose is given.
• Oxygen with a mask and a bag available.
• The opioid drawn up in a 1 mL syringe at a known concentration, clearly labelled.
• A laxative and an antiemetic prescribed at the same time as the opioid — not afterwards.
• A current creatinine with the eGFR, the weight, the age and the medication list.

Always dilute morphine 10 mg/mL to 1 mg/mL (1 mL made up to 10 mL with sodium chloride) before intravenous titration. Half of all opioid dosing errors arise at the dilution step, and an undiluted syringe of 10 mg/mL makes small adjustments impossible.

Procedure

Intravenous titration in acute severe pain

flowchart TD
  A[Severe acute pain in an adult. Venous access and naloxone to hand] --> B[Assess the pain with an NRS or VAS. Give paracetamol and, if appropriate, a COX inhibitor in parallel]
  B --> C{Risk group}
  C -- "An adult under 75, opioid-naive, with unimpaired breathing" --> D[Morphine 2.5 to 5 mg IV slowly]
  C -- "Over 75, frail, hypovolaemic, on a benzodiazepine, or an eGFR under 30" --> E[Morphine 1 to 2.5 mg IV, or choose oxycodone 1 to 2 mg IV]
  D --> F[Wait 5 to 10 minutes. The full effect of an IV dose comes only after 10 to 15 minutes]
  E --> F
  F --> G{Assess the pain, the respiratory rate and the level of sedation}
  G -- "Persisting severe pain, respiratory rate above 10, sedation score 0 to 1" --> H[Repeat the same dose]
  H --> F
  G -- "An acceptable level of pain at rest and on movement" --> I[Stop the titration. Add up the dose given as a starting point for the continuing prescription]
  G -- "Incipient sedation, sedation score 2, or a respiratory rate of 8 to 10" --> J[Stop the titration. Monitor. Consider another pain mechanism and adjuvant treatment]
  G -- "A respiratory rate below 8 or a sedation score of 3" --> K[Manage as opioid-induced respiratory depression]
  I --> L[Monitor the respiratory rate and the level of sedation for at least 30 minutes after the last dose]
  J --> L

Practical points during titration:

• Give the injection slowly over at least a minute; a rapid injection causes nausea and a fall in blood pressure without better analgesia.
• Flush the cannula before and after every dose, otherwise the dose does not arrive until the next flush.
• Assess the pain both at rest and on movement. A patient who is pain-free lying still but screams when turned has not finished being titrated.
• Expect an opioid-naive adult to need 5–15 mg of morphine in total. If more than that is required without effect, reconsider the pain mechanism instead of continuing to increase the dose.
• The level of sedation is scored on a four-point scale: 0 fully awake, 1 drowsy but easily roused, 2 sedated but rousable, 3 deeply sedated and not rousable. Sedation precedes respiratory depression and is the early warning sign.

Choice of agent

Avoid codeine and tramadol in severe pain. Both require activation by CYP2D6, which is absent in 5–10 % of the population and markedly upregulated in others; the effect is therefore unpredictable in exactly the direction that is dangerous.

From titration to a regular prescription

1. Add up the total dose that was required to achieve freedom from pain during the titration.
2. Estimate the daily requirement from this and from the expected course of the pain.
3. Give a short-acting preparation as required in the first instance during the first few days. Do not start a modified-release preparation in an opioid-naive patient with acute pain — the dose cannot be taken back when the sedation comes.
4. Once the daily requirement has been stable over two days, half of the daily dose can be given as a modified-release tablet twice daily.
5. The breakthrough dose is one sixth to one tenth of the daily dose — the lower proportion at high daily doses and in older people. An oral extra dose can be repeated after an hour, a subcutaneous one after 30 minutes.
6. Write the stop date and the tapering plan into the same prescription as the initiation.

Equianalgesic conversion

The table is based on the conversion guidance of the drug and therapeutics committees. The doses are daily doses and apply to opioid-tolerant patients.

The key figures behind the table, useful for mental arithmetic:

• Oral morphine to parenteral morphine: divide by 3 (30 mg PO ≈ 10 mg IV).
• Oral morphine to oral oxycodone: divide by 1.5–2.
• Oral oxycodone to parenteral oxycodone: divide by 2.
• Morphine and oxycodone are equivalent parenterally, even though oxycodone is twice as potent orally.
• Parenteral hydromorphone is 5 times as potent as parenteral morphine.
• Fentanyl is around 100 times as potent as morphine, but the patch is dosed via the table, not via the factor.

flowchart TD
  A[An indication for an opioid switch: adverse effects, renal failure, or no working oral route] --> B[Add up the whole daily dose of the current opioid, both the modified-release dose and all extra doses]
  B --> C[Look up the corresponding daily dose of the new drug in the conversion table]
  C --> D[Reduce to 50 to 70 per cent of the equianalgesic dose because of incomplete cross-tolerance]
  D --> E{A high dose, old age or a frail patient}
  E -- Yes --> F[Choose 50 per cent and set the breakthrough dose at one tenth of the daily dose]
  E -- No --> G[Choose 50 to 70 per cent and set the breakthrough dose at one sixth of the daily dose]
  F --> H[Make the switch outright. Do not taper the old drug in parallel]
  G --> H
  H --> I[Reassess after 24 hours and adjust the daily dose in steps of 20 to 30 per cent]
  I --> J{A fentanyl patch}
  J -- Yes --> K[The full effect comes only after 12 to 24 hours. Cover with repeated extra doses during the first 24 hours]
  J -- No --> L[Continued assessment at every ward round]

The reduction for incomplete cross-tolerance is mandatory. Tolerance to one opioid transfers only partly to another, and most serious overdoses on switching opioids are due to the equianalgesic dose being given as it stands. Conversion tables are a guide — the uncertainty grows with the dose.

Mandatory accompanying prescriptions

• A laxative from day one, for everyone. The bowel develops no tolerance to the constipation. Combine an osmotic agent (macrogol) with a stimulant (sodium picosulfate or senna glycosides). For treatment-refractory opioid-induced constipation there are peripherally acting opioid antagonists.
• An antiemetic as required, not routinely as a regular prescription. Nausea affects about a third of patients, is worst during the first few days and subsides as tolerance develops. Metoclopramide or low-dose haloperidol are the first choices; ondansetron worsens the constipation.
• Paracetamol as a baseline prescription, and a COX inhibitor when it is not contraindicated — both reduce the opioid requirement.
• Itching is not treated with an antihistamine in the first instance; it is usually opioid-induced and responds best to a dose reduction or a change of drug.

Complications

• Respiratory depression — the only potentially fatal one. The risk is greatest in the opioid-naive, in older people, with a concurrent benzodiazepine or gabapentinoid, in untreated sleep apnoea, and when several routes of administration are combined.
• Sedation and confusion, particularly in older people.
• Constipation in essentially everyone.
• Nausea and vomiting.
• Urinary retention — check the bladder in a patient who has not passed urine for several hours.
• Itching, dry mouth, sweating, myoclonus.
• Hypotension, above all in hypovolaemia and after rapid injection of morphine.
• With longer treatment: hyperalgesia, hypogonadism, adrenal insufficiency, tolerance and dependence.

Opioid-induced respiratory depression

flowchart TD
  A[A respiratory rate below 8 per minute, or a sedation score of 3, deeply sedated and not rousable] --> B[Call for help. Open the airway, rouse the patient, encourage them to breathe]
  B --> C[Give oxygen and check the saturation. Assist ventilation with a bag and mask in apnoea]
  C --> D[Dilute naloxone 0.4 mg per mL with sodium chloride to 0.04 mg per mL]
  D --> E{Is the patient on opioids for pain}
  E -- "Yes, a pain patient or a palliative patient" --> F[Give 0.04 to 0.1 mg IV. Repeat every minute until the respiratory rate is above 10]
  E -- "No, suspected poisoning with an unknown dose" --> G[Give 0.2 to 0.4 mg IV. Repeat if there is no effect. Consider the intramuscular or intranasal route if there is no venous access]
  F --> H{An effect within a few minutes}
  G --> H
  H -- No --> I[Give further doses up to a total of 2 mg. If there is no effect at all: reconsider the diagnosis. Other causes of unconsciousness]
  H -- Yes --> J[Continued monitoring for at least 2 hours, longer with a modified-release preparation, a patch or methadone]
  J --> K[Naloxone has a shorter duration than the opioid. Expect a relapse and be prepared for a repeat dose or an infusion]
  K --> L[Review the analgesia. Reduce the dose, change the drug, and look for a concurrent benzodiazepine or renal failure]

Titrate naloxone against the respiratory rate, never against wakefulness. Complete reversal in a pain patient causes withdrawal, agitation and a total breakthrough of pain that is very hard to bring back under control. With a fentanyl patch, the patch must be removed, but the depot in the skin continues to release drug for many hours — the monitoring must follow the duration of the opioid, not that of the naloxone.

Aftercare and follow-up

After intravenous titration, the respiratory rate and the level of sedation are monitored for at least 30 minutes after the last dose, and longer in older people, in renal failure and with concurrent sedatives. Assess the pain again after an hour.

At every contact during ongoing treatment:

• Pain assessment and function — is the patient getting up, sleeping, eating?
• Bowel function and the effect of the laxative.
• The respiratory rate and level of sedation when the dose is increased.
• Creatinine in older people during longer treatment.
• The total daily dose, including all extra doses, calculated in morphine equivalents.
• The tapering plan and the stop date at every repeat prescription.

On discharge after acute pain: prescribe the smallest quantity that covers the expected requirement, never a modified-release preparation as a regular prescription without follow-up, and document who is responsible for stopping it. Advise the patient not to drive in the initial phase, and about the risk of combination with alcohol and benzodiazepines.

Common pitfalls

• A fixed dose instead of titration. An opioid dose that is not assessed is a guess.
• The next dose given too soon. The full effect of an intravenous dose comes only after 10–15 minutes; if the dose is repeated after two minutes the effects stack up and the respiratory depression arrives when the patient has already been left alone.
• Morphine at an eGFR below 30. The active metabolite accumulates and causes late, prolonged sedation. Choose oxycodone or hydromorphone.
• The equianalgesic dose given as it stands when switching drugs, without a reduction for incomplete cross-tolerance.
• A modified-release preparation in an opioid-naive patient with acute pain — the dose cannot be taken back, and the prescription stays.
• The laxative is forgotten. Constipation is the commonest reason for patients stopping their analgesia.
• Naloxone titrated against wakefulness instead of against the respiratory rate.
• Monitoring stopped once naloxone has taken effect. The duration of naloxone is 30–60 minutes, shorter than that of most opioids.
• A concurrent benzodiazepine or gabapentinoid is overlooked — the combination is the commonest background to opioid-related deaths.
• Analgesia withheld in the acute abdomen. That delays the diagnosis rather than assisting it.