A. WHO ladder approach
The selection of the appropriate analgesic therapy is based on the interplay of the intensity of each patient's pain and current analgesic therapy. Pain intensity can be measured reliably in most patients* with the use of written or verbal numerical rating scales. Pain that is rated 5 or higher on a scale of 0 to 10 interferes with the quality of life and is defined as substantial pain. Pain ratings of 1 to 4 correspond to mild pain; of 5 to 6, to moderate pain; and of 7 to 10, as severe pain. The Three-Step Analgesic Ladder of the World Health Organization uses these three categories of pain to guide analgesic drug therapy (see Figure 1).
Patients receiving no analgesic therapy, who have mild-to-moderate pain should be treated with nonopioid analgesic drugs (step 1). If a patient has mild-to-moderate pain despite taking a nonopioid analgesic, the dose of the nonopioid analgesic should be maximized and a step 2 opioid analgesic (a "mild" opioid such as codeine, hydrocodone or oxycodone) should be added. Patients who have moderate-to-severe pain despite therapy with step 2 opioids require an increase in the dose of the opioid or, if that is not feasible, a change to a step 3 opioid (a "major" opioid such as morphine, hydromorphone or fentanyl).
This method can effectively relieve pain in 80 to 90 percent of patients. Many experts recommend a step 2 opioid as initial therapy for patients with moderate pain and may initiate therapy with a step 3 opioid when pain is severe. Patients who have mild-to-moderate pain persisting while taking a step 3 opioid should have the dose of that opioid increased to an effective level (Levy, 1996).
*Some patients use numbers differently. For these exceptions, pain rated as "4" may be severe, or pain rated as "8" may be very responsive to mild opioids. Clinical judgment is required.
B. Nonopioid analgesics
Nonopioid analgesics include acetaminophen, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). All of these agents have a ceiling effect in analgesia (a maximum dose beyond which analgesic effect does not increase), and all have potential for severe adverse effects.
Acetaminophen is a useful analgesic whose mechanism of action is poorly understood. Excessive doses can cause serious, even fatal, hepatic injury.
NSAIDs (including aspirin) may also be useful analgesics. They work by inhibiting cyclooxygenase (COX), the enzyme that converts arachadonic acid to prostaglandins. NSAIDs vary in their COX-2 selectivity. COX-2 is the enzyme produced in acute inflammation, COX-1 is the one related to many of the adverse effects of the NSAIDs: gastric irritation, renal insufficiency, platelet aggregation inhibition.
C. Opioid analgesics
In 1682 Sydenham said: "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium," and it is still true over 300 years later.
Most of the opioids (except methadone and meperidine) have similar first order pharmacokinetics. They are conjugated in the liver and excreted (90 ~ 95%) by the kidney. Peak plasma concentrations are achieved rapidly: 60 ~ 90 minutes after oral administration; 30 minutes after subcutaneous or IM injection; 6 minutes after IV administration. With normal renal clearance, all have half-lives of 3 ~ 4 hours.
If an immediate-release opioid is given orally for continuous (or stable) pain, it should be dosed every 4 hours. All patients on oral opioids should have access to "prn" or "breakthrough" doses in addition to their regularly scheduled doses. A good rule-of-thumb for breakthrough doses is 10% (5 ~ 15%) of the 24 hour total dose, although some patients may need more.
If pain is uncontrolled after 24 hours (or less if pain is severe), increase the regular dose by 25 ~ 50% for mild to moderate pain and 50 ~ 100% for severe pain.
When a stable 24 dose has been achieved with good pain relief, extended- or sustained-release preparations may be used. Simply divide the 24 hour dose by the dosing method (usually q 12 hours) to calculate the dose.
There is NO MAXIMUM DOSE for opioids: there is no ceiling effect for analgesia and doses are limited only by side effects.
c. Opioid allergy
True anaphylactic reactions to opioids are very rare. Urticaria and broncospasm are more commonly direct effects than allergies. Many side effects are often confused with allergic reactions, but they are adverse effects that are generally easily managed. If true allergy is suspected, an opioid from a different class may be tried.
2. Mild opioids
- inadequate for severe pain
- also limited by a short duration of action and being available p.o. only
- all are full mu agonists with relatively low analgesic efficacy.
- all are generally administered as fixed-dose combination products with aspirin or acetaminophen. When using these products, the toxicity of the non-opioid limits the dose of the opioid that can be administered daily.
- most constipating of all opioids at equianalgesic doses
- only available in combination products with aspirin or acetaminophen
- similar to morphine in potency and duration of action
- somewhat lower adverse effects (GI and CNS effects)
- relatively newly available in U.S. as single drug and as sustained release. This allows it to be used at higher doses, so it can also be considered a "major" opioid
3 Major Opioids
a. Morphine is the most commonly used opioid because:
- no narcotic is more effective
- it has a simple route of metabolism with minimal accumulation of clinically significant metabolites (morphine 6-glucuronide is an active metabolite with a longer half-life than its parent drug. Particularly when renal clearance is compromised, it may accumulate and have CNS side effects.)
- it is effective orally
- sustained release oral preparations are available
- a wide array of other preparations and doses of morphine are available, making it easy to titrate and to change routes of administration.
- commonly used as transdermal preparation (Duragesic patches)
- transmucosal preparation also available (lozenges and lollipops)
- also available for parenteral use (very short acting)
- reduced respiratory depression
- pharmacology is similar to morphine: similar efficacy, also simple route of metabolism, also effective orally
- useful in patients with idiosyncratic reactions / side effects to morphine
- no sustained release form available yet in the U.S. (although a new sustained release product is expected to be released soon)
- may be more effective than other opioids for neuropathic pain because of NMDA receptor activity
- difficult drug to manage because:
- has long and variable half-life, with slow onset of analgesia
- also has active metabolites with even longer half-lives (55 hours) - it takes 2 weeks to reach steady state
- accumulation can result in prolonged sedation and difficulty in managing fluctuations in pain
- best used ONLY by experts
e. Meperidine (Demerol) is a poor choice for chronic pain therapy because:
- Poor oral absorption (40%)
- Short duration of action (half-life 3 hours or less)
- Principal metabolite (normeperidine) is not analgesic but causes neurotoxicity (tremor, dysphoria, seizures). Normeperidine has a longer half-life than meperidine, thus, it accumulates. It is renally excreted, thus particularly problematic with renal compromise (elderly patients, renal disease, etc.)
Click here to read more about "The Use and Misuse of Demerol"
D. Equianalgesia tables
Equianalgesia tables are used when switching from one opioid to another, or when switching routes of administration. This helps to minimize problems related to underdosing or overdosing. Remember, "equianalgesia" simply refers to how much of drug A is needed to provide the same pain relief as x amount of drug B (note that "potency" refers only to the amount of the drug needed to achieve a given effect, not to its overall ability to relieve pain).
Comparative values are approximate and are achieved by consensus from very limited evidence. Therefore, you must clinically titrate. The only one who can really define the equianalgesic dose is the patient.
If changing opioids because of poor pain relief suspected to be due to tolerance, reduce the dose by 50% to convert.
Charts give values that apply to repeated administration in patients with chronic pain, not to occasional acute use.
IV values should mainly be used when converting from IV to other forms of administration - if starting IV use, always use small doses frequently and titrate up. This is particularly true when using IV administration because of poor pain control with oral administration.