Dosing Of Opioids In Tumor Pain

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In the treatment of acute pain after trauma or for the elimination of pain after surgery, central analgesics usually are given parenterally. This is in contrast to chronic pain, e.g. in tumor related pain, where the oral administration is advocated. This method relieves the physician from the necessity to inject the analgesic, it results in autonomous and self-regulation of the patient, it is cheaper and guarantees a stable blood plasma concentration, with the consequence of constant receptor occupancy [4]. New galenic preparations with a controlled release or extended release formulation are available, which result in a constant release of the pharmacologically active agent and a long lasting concentration of the active compound in the blood plasma, e.g. controlled release morphine sulfate (MS Contin® tablets 105/30/60/100/200 mg, Oramorph® 30/60/100 mg, Kadian® 20/30/50/60/100 mg, Ainza® 30/60/90/120 mg) extended release oxycodone hydrochloride (OxyContin® SR 10/20/40 mg) or extended release hydromorphone hydrochloride (Palladone® SR 4/8/16/24 mg). In addition, there is a long lasting sublingual preparation of buprenorphine (Buprenex® 4/8 mg) all of which possess the advantage that the analgesic has to be given only twice or even once a day.

While the mean dose of buprenorphine is one sublingual tablet every 8 h, MS Contin 30 it should be take one tablet every 8-12 h. However, when using Morphine long acting 30 mg, the dose is one tablet every 12 h, and when taking MS Contin, 60 mg every 24 h.

An even longer duration of action is possible through the use of a transdermal opioid patch where the active compound is administered transdermally over a period of 72h, e.g. the fentanyl transdermal therapeutic system (fentanyl TTS; Duragesic®) or the buprenorphine transdermal therapeutic system(buprenorphine-TDS; TranstecPro®).

The following recommendations are given when titrating the individual dose of an opioid to effect:

• Use only oral, controlled/sustained-release formulations of the agent. This results in long-lasting and stable plasma concentrations, a long-lasting occupation of the opioid receptors, which is followed by a long-lasting blockade of nociceptive afferents (Table IV-3).

• Titrate to the desired analgesic effect by increasing the dose 25%-50% and not by a reduction in the dosing interval (Fig. IV-3).

• The correct dose is reached, once the patient has sufficient pain relief.

• The dose of the opioid therefore has to be increased until pain subsides, or significant side-effects like sedation or a decline in respiratory rate below 12/min should prevent the physician from further dose increase. In the latter the dose and the type of the opioid have to be re-evaluated.

• Give the opioid only orally (administration by the mouth).

• Choose the opioid according to its pharmacokinetic half-life using a prescription with fixed time intervals (i.e. every 6h, 12 h, or 24 h - around the clock medication).

• Evaluate efficacy by using a non-verbal rating scale for pain intensity, for instance the VAS (visual analog scale where 0 denotes no pain and 10 reflects unbearable, excruciating pain).

• Choose an opioid for initial treatment that is related to the intensity of pain. For instance, pain rating with a visual analgesic score of > 7.0 demands an opioid of Step 3 in the analgesic ladder (WHO recommendation).

• In addition, always prescribe a laxative with the opioid since all opioids induce constipation.

• Inform the patient on the possibility of breakthrough pain. Such pain episodes are best treated by the additional "rescue medication" of a fast acting compound such as morphine immediate release (MSIR tablets 15/30 mg, MSIR capsules u>

Table IV-3. Opioid analgesics (pure agonists and partial agonists) used for the treatment of chronic pain

Morphine like opioids

Equi-analgesic doses

Duration of action (h)

Oral bio-availability (%)

Morphine

Sustained-release morphine Controlled-release morphine

Hydromorphone Oxycodone

Sustained-release oxycodone Oxymorphone

Meperidine (pethidine) Not used for cancer pain due to toxicity in higher doses and short half-life Diamorphine

10 s.c. -No oral formulation available

Analgesic action due to metabolites,

Twice daily administration

Once-a-day administration 1-2

8-12

20-30 20-30

20-30

30-60

Same as morphine

Levorphanol

Methadone

Risk of delayed toxicity due to accumulation; useful to start dosing on p.r.n. Codeine

Propoxyphene HCI or napsylate, toxic metabolite may accumulate, combined with non-opioid Hydrocodone

Only available in combination with acetaminophen Dihydrocodone Only available combined with aspirin or paracetamol in some countries Fentanyl buccal Fentanyl-transdermal

Buprenorphine-transdermal

With long-half-life; accumulation accurs after beginning 20 p.o.

Usually combined with non-opioid

100-800 fig ratio oral morphine: transdermal fentanyl of 100:1

ratio oral morphine: transder.

buprenorphine 100:1

12-16

High interindividual variability

13-22

Same as morphine

15 min 65% bioavailabiity

48-72

48-72

Ongoing pain additional 10-25%

Ongoing pain additional 10-25%

Ongoing pain

Pain relief additional 10-25%

additional 10-25%

Ongoing pain

Pain relief additional 10-25%

Pain relief

6h time

Figure IV-3. Algorithm for titration of the individual dose of an opioid necessary for the alleviation of pain

25/30 mg, MSIR solution 20mg/ml, 10mg/5ml, 20mg/5ml) or oxycodone immediate release (OxylR 5 mg). In addition oral transmucosal fentanyl citrate (OTFS) lozenge can be advocated (Actiq® 200, 400, 600, 800, 1200, 1600 ^g), which acts via rapid absorption through buccal mucosal membranes.

• In chronic pain management always start with the lowest available dose of an immediate release formulation. Thereafter, the dose is titrated to effect (Table IV-3). If, however, prior to therapy, the patient had been exposed to an opioid with low potency (i.e., meperidine, codeine) or an agonist/antagonist (i.e., pentazocine, butorphanol), the starting dose is 5 mg morphine immediate release. In case of insufficient pain relief 50% of the previous dose is added to the subsequent one. If, however, the patient is pain free after the first dose, the next dose should be reduced by 50%.

• Because of their short duration of action, opioids such as fentanyl, alfentanil or sufentanil, should be omitted as a basic opioid medication since their application interval is between 15 and 30min. This is in contrast to breakthrough pain, where a fast-acting and short-lasting opioid is given by an alternating route. For administration of a fast-acting opioid, the following alternatives are possible: transmucosal fentanyl lozenge, fentanyl effervescent buccal tablets, inhalation of liposome encapsulated fentanyl, inhalation of dry power fentanyl, or inhalation of morphine by means of a breath activated inhaler. All these newer techniques ideally can be used to counteract painful episodes of breakthrough pain (see more in chapter new developments in chronic pain therapy; page 380ff).

• Unless monitored by means of pulse oximetry and/or continuous surveillance, potent opioids should not be given intravenously in order to titrate to the desired analgesic effect, as respiratory depression often is seen immediately after an i.v. injection [5].

• Opioids such as codeine, oxycodone, morphine and merperidine on the average have to be given at in interval of 2-3 h, while pentazocine (Talwin®) is given every 4h. Contrary, controlled release morphine (MS Contin®) as well as buprenorphine (Buprenex®) are given every 8-10 h. Especially the buccal mode of administration of buprenorphine is of advantage, since the first-pass effect through the liver is by-passed resulting in a lesser rate of metabolism, a higher bioavailability and lesser amounts of the active agent. By using a special retarded technology, the administration interval of oral morphine slow release (MS Contin®) or morphine sulfate slow release capsules (Oramorph® 30/60/100 mg), which usually is between 8-12 h, can be prolonged by using the morphine sulfate sustained release capsules (Kadian® 20/30/50/60/100 mg). Dosing intervals can be extended once every 18-24 h, while use of extended release morphine sulfate formulation results in a one dose per 24 h.

Another opioid, methadone because of its specific pharmacokinetic profile, also inherits a long duration of action. While the levorotatory enantiomer (l-methadone) is about twice as potent as the racemic d,l-methadone, it is not available in the US, where the racemic mixture can only be prescribed (Dolophine® 10 mg). Because of its high volume of distribution the agent has the longest duration of action being > 24 h with a plasma half-life of up to 55 h [6]. The latter is related to its accumulation in the peripheral storage sites (skin, muscle, fat, connecting tissue), which act like a reservoir and from which the opioid is being released into the central blood compartment in a continuous fashion. However, due to its large volume of distribution, this opioid is difficult to handle, which is why it is not considered as the first agent of choice. Because titration to effect is only be achieved after 2-3 days this easily results in an overdose. Also, due to the large individual variability in plasma half-life between 8 and 80 h, methadone is not regarded as the analgesic of choice when an opioid-naive patient is given the drug for the first time. It however, has the highest cost-effectiveness and represents a valid alternative, if tolerance to morphine or to transdermal fentanyl (Duragesic®) develops or when the patient has neuropathic pain. This latter implication is derived from the fact that methadone also inherits a small, but clinically relevant antagonistic action at the excitatory N-methyl-D-aspartate (NMDA) receptor, which results in a reduction of the usual high dosages of other first-line opioids.

It should be noted that aside from morphine, other opioids, due to their specific pharmacokinetic profile, present a valid alternative to the historically oldest opioid morphine. Characterized by a long duration of action, the controlled-release formulation of oxycodone (OxyContin®) and the controlled-release preparation of hydro-morphone (Palladone®) have potential advantages when compared to morphine:

1. Contrary to morphine, oxycodone has an oral bioavailability of 60%-80% and hydromorphone a bioavailability of 40% (Table IV-3). Such higher fractions of an administered dose of the medication that reach the systemic circulation results in lesser doses necessary for pain relief.

2. Both opioids are characterized by minor quantities of pharmacologically active metabolites followed by less important side effects (Fig. IV-4). This is in

Morphine

Morphine

0H Morphine-6-G!ucuronide Hydromorphor»

Figure IV-4. Metabolism of morphine via glucuronisation at the sixth position of the molecule. Due the double binding metabolism of hydromorphone is not possible resulting in lesser metabolites contrast to morphine, where hallucinations, nausea, vomiting, and/or marked sedation regularly are observed with increasing dosages, necessary for pain relief, resulting in a limitation of the administered dose. 3. Both agents have a short onset of action averaging between 1 and 2h which is in contrast to controlled-release morphine which needs at least 3 h to reach peak effects.

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