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Pharmacological Treatment of Cancer Pain

Essentials

Therapies that are effective against the cancer itself, such as antineoplastic agents, radiotherapy and surgery, often also relieve pain efficiently. If these treatments are not sufficient alone or if they cannot be used, pain is managed with medications or regional anaesthesia. Psychosocial support is an essential part of cancer pain management.
A stepwise approach to treatment methods in comprehensive cancer pain management is presented in picture 1.
1. Treatment is started with a NSAID or with paracetamol, unless these are contraindicated.
2. An opioid is added when the pain becomes more severe (and the ensuing constipation and other adverse effects are treated as well).
3. Pain induced by nerve damage is treated with tricyclic antidepressants or SNRIs and/or gabapentinoids (gabapentin and pregabalin).

Principles

The principles of pain management
- Effectiveness
- Feasibility
- Continuous pain relief at a stable dose by using a sustained-release drug
- Management of pain peaks with a rapid-acting drug
- Minimization of adverse effects by changing the opioid or route of administration or by managing them with suitable drugs
- Regular follow-up of the therapy
  - Pain assessment
  - Is pain relieved with the prescribed drug and dose? If it does not:
    - Has the patient taken / been given the prescribed drugs?
    - If not, why (fears, adverse effects)?
    - Is the drug absorbed? Does another drug inhibit the effect of the analgesic drug?

NSAIDs Nsaids for Cancer Pain

NSAIDs are more effective than paracetamol in pain relief.
The efficacy of different NSAIDs in the management of cancer pain has not been compared. In the range of recommended doses, a clear dose-response has been shown for various NSAIDs (better pain relief with higher doses).
Adverse effects to be considered include hypersensitivity and effects on gastric mucosa, platelet function, renal circulation and heart function.
- During treatment with some cytotoxic drugs (e.g. methotrexate) only paracetamol is safe to use.
- Gastric irritation can be alleviated with sucralfate, H₂ antagonists, proton pump inhibitors (omeprazole, lansoprazole and pantoprazole), and with a prostaglandin E₁ analogue (misoprostole).
- Selective COX-2 inhibitors (coxibs) cause less GI damage and do not prevent thrombocyte aggregation compared with traditional NSAIDs. As to renal function, they have no advantage over other NSAIDs. Coxibs are not recommended for patients who have an increased risk of myocardial infarction Safe Use of Non-Steroidal Anti-Inflammatory Drugs (Nsaids). As regards pain relief, selective COX-2 inhibitors do not provide any additional benefit except for their long duration of action. Inhibition of COX-2 may inhibit the growth of cancer cells.
Different NSAIDs should not be administered simultaneously. If the drug is not efficient alone, an opioid should be combined with it.
An NSAID should be continued with the opioid if it has been beneficial as these two drugs with different modes of action usually give better pain relief when they are combined. NSAIDs are particularly effective for pain caused by skeletal metastases.

Opioids

Severity of pain determines which opioid should be used. Opioids can be classified into three groups on the basis of their efficacy and ceiling effect:
1. Weak opioids
  - Codeine (only in combination products) and tramadol. Both are prodrugs that require a functional CYP2D6 enzyme in order to function as opioids.
2. Medium-strength opioids
  - Buprenorphine
3. Strong opioids (in alphabetical order)
  - Fentanyl (as a matrix membrane patch or transmucosal resoriblette or spray)
  - Hydromorphone
  - Methadone
  - Morphine
  - Oxycodone
Interindividual differences in adverse effects and efficacy may be significant. If an adequate dose of one opioid is not effective, change to another.
Morphine is still considered as the first-line strong opioid for oral administration. In Finland, however, oxycodone has replaced morphine as the most used strong opioid.
Combined sustained-release tablets containing oxycodone and naloxone are available (naloxone is an opioid antagonist which is metabolized in the liver, but in the gut it prevents constipation caused by oxycodone). Different strengths exist, but the ratio is always 2:1 (e.g. 5 mg oxycodone, 2.5 mg naloxone).
Opioids very rarely cause psychological dependence in cancer patients.
Because of neuroadaptation (physiological dependence) sudden discontinuation of opioid medication leads to withdrawal symptoms (this is not psychological dependence). Therefore, opioids should not be discontinued abruptly.
If the pain is opioid-sensitive (alleviated with opioids), the effect will not necessarily wear off even if the patient uses the drug for several years. The effect may wear off, in which case the dosage needs to be increased. Changing the opioid to another opioid may increase the effect. The opioid dosage should not be increased, however, without considering the reasons behind the increased pain (severe mental anxiety, for example). High opioid doses may increase pain sensitivity (hyperalgesia). Other adverse effects also occur more frequently with higher dosage.
Need for opioids may increase as the disease progresses and pains become more intense, as an effect of other drugs or due to the development of tolerance.
- E.g. drugs inducing hepatic metabolism, such as rifampicin and carbamazepine, decrease the effect of oxycodone and methadone, and drugs inhibiting the action of CYP2D6, such as paroxetine, render codeine and tramadol ineffective as analgesics.

Constant pain relief and treatment of pain peaks

Morphine, oxycodone and hydromorphone are available as sustained-release tablets that are administered twice daily. The effect of sustained-release preparations begins within one to two hours.
Breakthrough pain requires rapid relief, which is achieved with morphine or oxycodone solution or with normal release oxycodone tablets. The additional dose for breakthrough pain is one sixth of the normal daily dose of the corresponding preparation. The fastest pain relief can be achieved by transmucosal fentanyl, especially as nasal spray.

Avoid intramuscular injections!

Oral opioids are a more simple and humane option compared with intramuscular injections; a terminal-phase patient has little muscle tissue left, injections are painful and have to be repeated at 2-4-h intervals. A patient in poor condition has trouble learning to pull a small amount of the drug into the syringe and to inject it oneself.
Oral administration of a liquid opioid is as effective as i.m. administration, as long as the dose is sufficient.

Subcutaneous infusion

If the patient cannot take oral medication because of a GI obstruction or severe nausea, constant pain relief can be achieved with subcutaneous infusion. Both morphine (1/3 of the daily oral dose) and oxycodone (1/2 of the daily oral dose) can be given as a subcutaneous infusion.
- As an alternative to subcutaneous infusion, a paediatric Viggo^® cannula can be inserted subcutaneously and the drug is administered through it by boluses. This technique is used in hospital-at-home settings and also a lay caregiver can administer the drug.
An antiemetic can be administered concomitantly with the opioid infusion (haloperidol 2-5 mg/day).
Transdermal fentanyl administered through a matrix membrane patch is an alternative to subcutaneous infusion. The patch is changed every 72 hours (table T1).

Dose of transdermal fentanyl

Oral dose of morphine (mg/24h)*	Dose of transdermal fentanyl (µg/h)
<135	25
135-224	50
225-314	75
315-404	100

* The dose of oxycodone is on average 2/3 of the dose of morphine.

Problematic pains Gabapentin for Chronic Neuropathic Pain in Adults

Opioids as such do not always provide adequate pain relief. Pain caused by nerve damage or fractures may be problematic.
A cancer patient may have a purely neuropathic pain, e.g. polyneuropathy caused by antineoplastic agents. This pain is managed as neuropathic pain in general: with antidepressants (amitriptyline or nortriptyline 25-75 mg/24 h, duloxetine 30-60 mg/24 h, venlafaxine 150-300 mg/24 h) or antiepileptic drugs (gabapentin 900-3 200 mg or pregabalin 150-600 mg/24 h).
The tumour may compress or infiltrate nerve tissue. Management often requires large doses of opioids or regional anaesthesia (consult an anaesthesiologist).
In severe pain spinal drug delivery may be considered (local anaesthetic agent, opioid, alpha-2-adrenergic agonist such as clonidine, NMDA antagonist such as ketamine) and neurosurgical procedures
It is important to take psychosocial factors into account when treating cancer pain. Every cancer patient should have access to psychosocial support.

Examples of oral opioids

Codeine in combined preparations

Oral administration
Ibuprofen 200 mg + codeine 30 mg
Paracetamol 500 mg + codeine 30 mg
Approximately 10% of caucasians are "slow metabolizers" who do not metabolize codeine to morphine and the drug has no effect. The result is the same if the patient uses drugs that block the CYP2D6 isoenzyme which mediates the metabolizing of codeine into morphine.
Ultrarapid metabolizers efficiently convert codeine to morphine which in special situations may even lead to respiratory depression.

Tramadol Tramadol for Cancer Pain

Oral, intravenous or rectal administration
The weak opioid effect of tramadol is transmitted mainly by metabolites. Blocking of the CYP 2D6 isoenzyme prevents the formation of ”opioid metabolites”.
Tramadol inhibits noradrenaline re-uptake into nerve cells and increases serotonin secretion.
Nausea is the most common adverse effect.
Suitable also for the treatment of mild neuropathic pain
A combination product with paracetamol is also available (tramadol 37.5 mg/paracetamol 325 mg).

Buprenorphine

Sublingual or transdermal administration
Maximum daily dose is approximately 4.2 mg.
Buprenorphine is a partial opioid agonist. In high doses its analgesic efficacy may decrease as well as that of other opioids.
Dizziness and nausea are the most common adverse effects.
Adverse effects can be reduced by administering the drug transdermally (the membrane remains effective in 7 days if the dose is appropriate). The response is insufficient for severe pain.

Strong opioids

Strong opioids do not have specifically defined maximum doses, but large doses may cause e.g. sensitization of the pain system. If pain is alleviated by opioids, more relief is expected if the dose is increased. Therefore, only starting doses are given for strong opioids. The starting dose is determined by the intensity of pain and the patient's condition. Elderly persons are usually more susceptible than younger patients. If increasing the dose does not provide better pain relief, other options should be considered.

Fentanyl Transdermal Fentanyl for Cancer Pain

Transdermal or transmucosal administration
Fentanyl is a very potent opioid. Treatment with transdermal patches (matrix membrane patches) is suited only in patients whose pain is well managed. Fentanyl is not suited when the dose is first being titrated or when the severity of pain varies greatly during the day.
Pain relief begins within 12 hours after the first patch has been placed. When the patient changes from sustained-release morphine or oxycodone tablets to a fentanyl patch, the last tablet is given when the first patch is placed.
Fentanyl patch is indicated in patients who cannot take pain medication orally.
Fentanyl does not release histamine. It causes less constipation than morphine.
Fentanyl is poorly absorbed through the skin of a cachectic patient.
For choice of fentanyl patch, see table T1.
The patch is changed every 72 hours.
If the patient requires more than 3 or 4 of 100 µg/h patches/24 h, another drug or mode of administration should be chosen.
Rapid-acting fentanyl preparations for the treatment of breakthrough pain include nasal spray (most rapid), buccal soluble film or tablet and sublingual tablet.

Hydromorphone Hydromorphone for Cancer Pain

Oral, intravenous or subcutaneous administration, under special license also as injection-infusion liquid.
Parenteral dose is about one third of the oral dose.
Hydromorphone, like morphine, does not have CYP-mediated metabolism (like oxycodone has).

Methadone Methadone for Cancer Pain

Oral administration, under special license also parenteral administration
Orally administered methadone has a good bioavailability. It may be more effective than other opioids in the management of neuropathic pain.
Pharmacokinetics of methadone is complicated: only to be administrated by experienced personnel. Abundant interactions with other pharmaceuticals.

Morphine Oral Morphine for Cancer Pain

Oral, intravenous, subcutaneous, spinal or topical administration
Morphine is the basic opioid. With oral administration its bioavailability is poor and variable. The parenteral dose is usually about 30% of the oral dose. In renal failure, the dose must be reduced. Morphine is a potent releaser of histamine.

Oxycodone Oxycodone for Cancer Pain

Oral, intravenous or subcutaneous administration
The bioavailability of oxycodone with oral administration is good. The parenteral dose is usually about 1/2-2/3 of the oral dose. Adverse effects are the same as those of morphine. Some patients have less nausea and nightmares compared with morphine.
Oxycodone is also available in combination with naloxone.

Equipotent oral daily doses for the starting phase

Morphine 60 mg
Oxycodone 40 mg
Hydromorphone 8 mg
Methadone 10-15 mg
Fentanyl 25 µg/hour (transdermal membrane patch)
These doses are suggestive. Titration must be carried out individually. When the patient changes from one strong opioid to another after having used it even for a week, the dose relationships may vary unexpectedly.

The most common adverse effects of opioids

Sedation (usually alleviated after the starting phase)
Nausea (usually alleviated soon)
- Management: haloperidol 0.5-1 mg × 3. If nausea is severe and/or persists, try changing the opioid and, in complicated cases, the mode of administration
Constipation (unavoidable and persistent)
- Management: laxatives, e.g. sodium picosulphate (increases bowel motility) and lactulose (makes the faeces softer by increasing its fluid content through osmosis). If these measures do not provide sufficient response, methylnaltrexone (an opioid antagonist not crossing the blood-brain barrier) 8-12 mg subcutaneously every 2 days may be given. Another alternative is naloxegol which penetrates the blood-brain barrier poorly and is administered orally, usually 25 mg once daily.
- In one preparation, oxycodone has been combined with the opioid antagonist naloxone which only acts at the intestinal wall (metabolized in first pass by the liver).
Pruritus (usually a direct opioid receptor effect; morphine releases histamine, which may be the cause of pruritus)
Sweating (especially in association with fentanyl use)
Accommodation disturbance (difficult to read!)
Nightmares (both at night and/or during the day)
- Management: change the opioid or start haloperidol
Muscle cramps (particularly with high doses of morphine)
- Management: change the opioid, try benzodiazepines
Respiratory depression is usually not a problem if the dose is related to the amount of pain that in itself increases respiration. If the pain is suddenly alleviated by, for example, regional anaesthesia, respiratory depression may occur.
- Management: oxygen. Urge the patient to breathe. In emergency situations give naloxone intravenously e.g. 0.4 mg.
- Benzodiazepines make the respiratory depression caused by opioids worse.
The FDA has warned also about the following adverse effects of opioids: adrenocortical insufficiency, sex hormone deficidency, serotonin syndrome.
Opioids may suppress immune defence (morphine and codeine the most).
The benefit/harm ratio should be considered in a severly ill patient. Right dosing and concurrent use of other effective pain relief methods reduce the harms caused by opioids.

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Information ⬇

Editors

Pharmacological Treatment of Cancer Pain

Essentials

Principles

NSAIDs Nsaids for Cancer Pain

Opioids

Constant pain relief and treatment of pain peaks

Avoid intramuscular injections!

Subcutaneous infusion

Dose of transdermal fentanyl

Examples of oral opioids

Codeine in combined preparations

Tramadol Tramadol for Cancer Pain

Buprenorphine

Strong opioids

Fentanyl Transdermal Fentanyl for Cancer Pain

Hydromorphone Hydromorphone for Cancer Pain

Methadone Methadone for Cancer Pain

Morphine Oral Morphine for Cancer Pain

Oxycodone Oxycodone for Cancer Pain

Equipotent oral daily doses for the starting phase

The most common adverse effects of opioids

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