Rotation from One Opioid to Another

The Peripheral Neuropathy Solution

The Peripheral Neuropathy Program

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Therapy of chronic pain, according to present recommendations, advocates the principle of the analgesic ladder. With this principle in mind, chronic pain first is treated by a peripheral analgesic. If this medication is not suffficient for relief, no time should be lost and a weak opioid, which later can be replaced by a more potent compound should be used. By doing so, one has to realize that different opioids interact with different receptors, and that a combination of a pure ^-ligand with a mixed agonist/antagonist, also in long-term pain therapy, is considered a major pharmacological mistake. This is because any simultaneous administration of a mixed class opioid with a pure agonist results in the displacement of the pure ^-ligand at the receptor site, resulting in a decrease of the analgesic effect. If the patient receives an agonist/antagonist for pain therapy (e.g. pentazocine, butor-phanol), a more potent opioid with selective ^-characteristics (e.g. morphine), will not work accordingly and only after a wash-out phase, the new opioid is administered. During this time pain therapy is maintained by peripheral analgesics using derivatives from the class of non-steroidal antiinflammatory drugs (NSAIDs), which mediate their mode of action through inhibition of cyclooxygenase synthesis (COX-1, 2-inhibitors). Only after the elimination phase of the mixed agonist/antagonist, which may differ from one product to the other, slow titration with the new opioid

Table IV-13. Conversion from an oral opioid (24 mg/h) to the transdermal buprenorphine patch (u,g/h)

TranstecPro® /ug/A

33

52.5

70

87.5

105

122.5

140

Tramadol

150/300

450

600

Morphine oral

30/60

90

120

150

180

210

240

Oxycodone oral

30

60

90

120

Hydromorphone oral

4/8

12

16

20

24

28

32

Fentanyl TTS (ug/h)

2.5

50

75

100

Buprenorphine

0.4/0.8

1.2

1.6

2.0

2.4

2.8

3.2

sublingual sublingual is initiated (Table IV-13). For such purposes a slow release medication such as Oxycontin® SR presents several advantages as it is as effective as immmediate release oxycodone. The agent has to be given only twice a day compared to 4 times daily. It presents a lesser incidence in side effects such as nausea, vomiting, somnolence and dizziness all of which result in a better compliance of patients [75].

OPIOID ROTATION FROM MORPHINE TO BUPRENORPHINE OR METHADONE

Contrary to mixed agonist/antagonists the partial ^-agonist and K-antagonist buprenorphine due to its small number in receptors being occupied and the simultaneous high ^-affinity, still has significant receptor reserve. Pure ^-agonists such as morphine, fentanyl TTS or oxycodone can be added without any problems. The same holds true if the physician wants to convert from a pure ^-agonist morphine, hydromorphone or oxycodone to buprenorphine TTS (Transtec®), the transdermal form of the partial agonist which can be used for pain treatment. The following table can be applied for rotation, whereby certain patients need an individual lower dose than the calculated equivalent (Table IV-13).

On the other hand methadone represents a cost-effective alternative to oral morphine or transdermal fentanyl TTS, in particular when using its enantiomer levomethadone. This opioid especially is indicated, when tolerance development to the present opioid medication becomes obvious, a neuropathic pain component is present in the patient, and where high dosages of first-line opioids do not result in sufficient pain relief [76, 77, 78]. The rational for the use of methadone stems from the fact that this opioid also inhibits a NMDA-antagonistic profile and acts as a serotonin reuptake inhibitor [79, 80, 81]. Due to its special pharmacokinetic feature, characterized by a long elimation half-life, after a basic dose, the following doses are adjusted to effect. The following procedure is advocated when changing another opioid to methadone:

Day 1: The morphine dose is stopped and independent of the previous opioid dose, methadone 5.0-10.0 mg orally is given every 4h.

Day 2: When pain is not sufficiently attenuated, the dose of methadone is increased by 30% every 4h. When necessary, additional medication is given every hour until side effects of overdose become obvious.

Day 3: After 72 h the application interval is prolonged to 8h. Any additional medication is similar to the single dose given every 3 h.

Day 4: In case of insufficient pain relief the dose of methadone is increased further by 30% given every 8 h. Requirement medication is similar to the single dose, every 3 h until sufficient pain relief or side effects become apparent.

OXYCODONE AND HYDROMORPHONE -ALTERNATIVE OPIOIDS FOR PAIN RELIEF

Although morphine is considered a reference agent for therapy with opioids, it does not denote that this is the drug of first choice when treating pain. Because of the metabolites of morphine, i.e. morphine-6-glucuronide, which is produced between 4.7% and 11%, and of morphine-3-glucuronide, which accumulates between 57% and 74%, there is a reduction in efficacy (Fig. IV-27). Such decrease in analgesic potency cannot be explained solely by the elimination half-life which is longer than the parent compound morphine.

Decrease in analgesia during long-term application of morphine is explained by the accumulation of the metabolites, which results in toxic excitatory effect (Fig. IV-28). This in particular applies to elderly patients, who typically show a reduction in kidney function with reduced elimination resulting in an accumulation of the two metabolites and an increase in side effects. Thus morphine-3-glucuronide can induce agitation, myoclonia, and hyperalgesia which may end up in somnolence and even seizures [81, 82], and after morphine-6-glucuronide miosis, sweating, nausea and vomiting as well as opioid intoxication may be observed as this metabolite has a higher affinity to the binding site [83, 84].

When using morphine for pain therapy and when marked side effects are observed in the patient, one should consider rotation to another opioid. In such instances it is rational rotating to a more potent compound such as oxycodone, which does not result in pharmacologically active metabolites or to an opioid with a higher receptor specificity like hydromorphone, fentanyl or buprenorphine. Due to this higher receptor specificity there is more selective binding of ^-ligands with lesser side-effect, findings which are corroborated by Pasternak and coworkers in genetically transmutagenic mice, who demonstrated the existance of at least a dozen different ^-receptor isoforms [85]. The change to a different opioid such as the controlled release form of oxycodone (OxyContin®SR), hydromorphone (Palladone®SR), or transdermal fentanyl and buprenorphine respectively is of practical importance, because these agents inherit the following favorable characteristics: 1. Oxycodone has a small first-pass effect through the liver; and after oral intake 84% of the actual dose is available for the mediation of effects (high bioavail-ability). This also holds true for hydromorphone, which contrary to morphine, after oral ingestion has a bioavailability of up to 36.4%.

HO OH

Figure IV-27. The major metabolites of morphine, which are the cause for often observed side-effects during long-term morphine treatment

Figure IV-28. Due to the active renal clearance of morphine metabolites, there is an accumulation in the elderly especially when morphine is given over a longer period of time, as they demonstrate an age-related reduction in renal clearance

2. Oxycodone in addition to hydromorphone, does not result in the formation of pharmacologically active metabolites. This is in sharp contrast to morphine where metabolites like morphine-3- and morphine-6-glucuronide are formed. Such difference is of particular importance in patients with limited liver and/or kidney function which otherwise would result in an accumulation of metabolites with an ensuing state of confusion (Fig. IV-28).

3. The metabolites of oxycodone are oxymorphone and noroxycodone, which are only formed by 10%. Such a low concentrations result in clinically lesser side-effects. During hydromorphone the majority of the compound is metabolised by 39% to the pharmacologically inactive hydromorphone-3-glucuronide, which primarily is eliminated via the kidneys.

4. For the metabolites of oxycodone,oxymorphone and noroxycodone, there is an elimination which parallels a decline in plasma levels of the mother compound; it therefore does not result in an accumulation of metabolites.

5. Oxycodone and hydromorphone, in regard to their analgesic potency, do not show a ceiling-effect. The dose of the opioid can be increased whenever necessary and as the dose is increased, in each case this is followed by an increase in effect.

6. Oxycodone and hydromorphone in regard to the central nervous system, are characterized by fewer side effects. This in particular applies when comparing both compounds with morphine, where hallucination, sedation and tiredness often can be observed.

7. Controlled release oxycodone achieves a maximal analgesic effect within 1 h; this is in complete contrast to controlled release morphine, where a time period of up to 3-4 h is necessary for maximum effect. When using controlled release hydromorphone, the maximum analgesic effect is to be expected after 2.5 h.

8. Unlike morphine, oxycodone and hydromorphone do not possess a negative stigma. Due to the association of morphine and dependency development many patients are still afraid to use opioids on a regular scale and in sufficient amounts.

9. Oxycodone and hydromorphone are pure ^-agonists with very little affinity to the K-receptor. This is in contrast to buprenorphine, which is a partial ^-agonist and K-antagonist, and specifically is in contrast to morphine which interacts with several ^-isoreceptors. This presumption could be demonstrated in receptor binding studies where the metabolite of morphine, morphine-6-glucuronide demonstrated selective interaction with its own distinct receptor,which is responsible in the mediation of excitatory effects [86].

10. Oxycodone similar to hydromorphone induces a lesser constipating effect when compared to morphine.

11. When using oxycodone there is a much faster equilibrium of dose and desirable effect. This is particularly true for the onset of a maximum effect, which takes much longer when controlled release morphine (MS Contin®) is used and is of substantial advantage in patients with pain.

12. Oxycodone, fentanyl and buprenorphine are also suitable for therapy of neuropathic pain, which usuallly is characterized by opioid resistancy.

13. The conversion factor of oral morphine to controlled release oral oxycodone shows a ratio of 2:1. If, however, the patient is first treated with oxycodone (opioid-naive), it is advised to start with a lower dose in order to subsequently adapt to the next higher concentration. This course of action is only possible because the maximum effect of oxycodone can be judged within 1 h.

14. The conversion ratio of oral morphine to oral controlled release hydromorphone is 7.5:1. If however, the patient is first treated with hydromorphone (opioid-naive), it is advisable to start with the lowest concentration of hydromorphone and adapt to the next higher dose only when necessary.

15. If opioid therapy should no longer be necessary, a patient on a daily dose of 20-60 mg of controlled release oxycodone can be withdrawn immediately. Tapering down of the dose however is necessary in patients with daily doses higher than 60 mg.

16. When performing opioid rotation it has to be emphasized that the usual conversion scales, which are available for computation, because of the large inter-individual variability should only beused as arough estimate. When changing frommorphine to hydromorphone or rotating from morphine to fentanyl TTS or buprenor-phine TDS, it is conceivable that dose equivalency is only in one and not into both directions. Thus, when transferring oxycodone to morphine it does not correspond to the same dose relations when transferring from morphine to oxycodone. Therefore one should start with a low dose and quickly titrate up to the desired effect, which in the case with controlled release oxycodone can be achieved much faster as maximum receptor occupancy is reached within 1 h.

17. Because of pharmacologically inactive metabolites of hydromorphone, this agent particularly is indicated in pain therapy of the elderly patient.

18. Since elderly patients with chronic pain regularly demonstrate a reduction in kidney clearance, hydromorphone and buprenorphine offer several advantages as they are primarily metabolized by the liver and eliminated via the bile. Thus, serious side effects induced by the previous medication with morphine (i.e. dizziness, confusion, profound sedation, nausea) can be reduced by 80% [112] .

19. Because of functional impairment of liver activity in the elderly, one should start with half the usual recommended dose of oxycodone or hydromorphone.

20. In the elderly, multimorbid and cachectic patient with low plasma protein level, hydromorphone has attained special attention, because this compound demonstrates a low protein binding of only 8%. This is in marked contrast to fentanyl, which has a plasma protein binding of 90% and of buprenorphine with a binding capacity of 96% [38].

In summary, when changing from morphine to oxycodone, hydromorphone, or buprenorphine the following points have to be considered:

1. Start with the lowest dose of the opioid to switch to.

2. Rapidly titrate up to the desired effect for achieving a sufficient analgesia.

3. Generally, always switch to a more potent opioid with higher affinity for the opioid receptor. This particularly refers to morphine which is an opioid with little selectivity. Thus ^-opioid receptor mediated analgesia is less selective and specific than opioids with higher selectivity (e.g. oxycodone, hydromorphone, fentanyl buprenorphine) which are more suitable for rotation [115].

4. Do not rely on the equivalent doses derived from conversion scales.

5. When converting from morphine to oxycodone or hydromorphone, a stable analgesic effect only can be expected after 2 weeks. This is due to the time to excrete all active metabolites of morphine, such as morphine-6- and morphine-3-glucuronide. The higher potency of oxycodone in comparison to morphine seems to be based on the higher interaction of oxycodone at the K-receptor with lower intrinsic activity at the ^-receptor [87]. Also hydromor-phone, fentanyl and buprenorphine display a higher affinity to the with lesser K-receptor interaction than morphine, which results in a higher analgesic potency [115].

In the context of opioid therapy for chronic pain treatment, the following considra-

tions have to be recognized:

• It is of no advantage to give 2 weak and two potent opioids at the same time.

• A weak opioid can only be added to a more potent opioid, once there are episodes of pain increase such as in breakthrough pain.

• Generally the patient should be instructed to add an additional fast release dose of the regular medication once there is breakthrough pain.

• Short-lasting opioids, such as pentazocine or pethidine (meperidine, USP) should be avoided, because the dosing interval is too short.

• Simultaneous and/or sequential ingestion of an agonist/antagonist (e.g., penta-zocine, nalbuphine, dezocine) with a pure agonist (e.g., codeine, morphine) must be avoided. However, simultaneous administration of the partial ^-agonist, K-antagonist buprenorphine (Buprenex®) with morphine, due to its special receptor kinetics, is possible since this compound does not replace the previous one.

• An opioid should be given in regular time-intervals; the latter depends on the duration of action of the specific opioid.

• If there is an insufficient analgesic effect, with a sufficient duration of action, an increase in the dose is required.

• If there is a sufficient effect in potency, but a reduced duration of action, a reduction in dosing interval is required. In order to avoid such a setting, controlled release opioids with longer dosing intervals of up to 12 and 24 h, or a transdermal opioid system (e.g. Duragesic®, TranstecPro®) should be prescribed. Both have a duration of up to 72 and 92 h/patch, respectively.

• Selection of the type of opioid depends on the intensity of pain. The latter is evaluated using pain rating scales such as the numeric pain intensity or the visual analogue scale (VAS) where 0 = no pain and 10 = worst possible pain. If VAS is between 1 and 4 one should start with a non-opioid. If pain intensity is higher, (VAS between 5 and 6) a contolled release opioid with medium potency such as codeine, dihydrocodeine or tramadol is indicated. In such cases an active compound such as transdermal buprenorphine (TranstecPro®) may also be used because this substance in a reduced dose is sufficient for producing analgesia.

• A transdermal mode of administration should be considered if non-opioid analgesics are no longer effective. In cases with very intense pain (VAS 7-10), one should immediately start with an opioid of Level 3 in the WHO ladder (morphine, oxycodone, hydromorphone, fentanyl TTS or buprenorphine TTS).

• Rapidly titrate the dose of the opioids upwards to a point of sufficient pain relief.

• Together with the opioid, prescription of a laxative such as a fecal softener (Colace®), a hyperosmolar glycerin agent (MiraLax®, Fleet®Glycerin), a mineral oil enema (Fleet Enema ®) or a bisacodyl containing preparation (Fleet Biscodyl®) is mandatory.

• In the presence of neuropathic pain (pain due to chemotherapy, post radiotherapy pain, post surgical pain, plexopathy, paraneoplastic, radiculitis, post herpetic neuralgia, peripheral neuropathy of diabetic origin) additional medication which interacts at the NMDA-receptor (memantine, dextromethorphane, ketamine) or alternatively an antiepileptic of the second generation (gabapentin, lamotrigine, topiramate) and/or an antidepressive of the NASSA group (noradrenergic and specifically serotonergic antidepressant) like mirtazapine, and to a lesser degree a tricyclic antidepressant of the SSRI group (selective serotonin reuptake inhibitors) should be considered. Because of its simultaneous NMDA-antagonistic efficacy [116] the opioid methadone (Dolophine®) presents an alternative.

• When side-effects such as emesis are dominant, potent antiemetics such as low doses of a neuroleptic (Haldol® 0.5-1 mg) every 6-8 h or ondansetron (Zofran® 4 mg) are given.

• When marked sedation is troubling, the patient should receive an analeptic like dextroamphetamine, methylphenidate or modafinil.

• Additional corticosteroids are indicated in acute nerve compression, an increased intracranial pressure, anorexia, infiltration of soft tissue, distention of visceral organs and mood changes.

• When metastases of the bone are evident, biphosphonates are indicated.

• For break-through pain, the patient additionally receives fast release opioids, whereby the dose of the opioids is 5%-15% the entire daily opioid dose. The dosing interval should be long enough in order to take full effect. In case of controlled release morphine a liquid morphine solution, in case of transdermal fentanyl (Duragesic®) the oral transmucosal fentanyl citrate stick (OTFC; Actiq®), in case of transdermal buprenorphine (TranstecPro®) a buccal buprenor-phine tablet is administered.

• When oral therapy with opioids is insufficient or when side effects are dominant, change to another opioid (opioid rotation) is indicated. In certain cases change to methadone may be appropriate because the drug additionally blocks the NMDA-receptor and in addition results in a presynaptic inhibition of serotonine reuptake which results in potentiation of the analgesic effects [117].

• Once the patient is transferred to another opioid, in general the dose of the new opioids is reduced by 30%-50%. This is followed by titration of doses to the desired effect.

• As pure ^-ligands do not show a ceiling effect the dosage can be increased, titrating to a point of sufficient pain relief or side effects are not tolerated any more.

In extreme tumor-related pain, which cannot be controlled with the usual opioid medication, some authors (Bowlder, Mountain Seler, 1984, personnel communication) recommend a morphine-haloperidol-mixture given every 4h. For preparation, use 5 ml of distilled water, and add 10-40 mg of morphine together with 0.25 mg of haloperidol.

As an ULTAMA RATIO epidural opioids via an external or internal pump, combined with a local anesthetic or an a2-agonist like clonidine is possible. This is a final therapeutic option, whereby regional pain therapy is initiated by means of opioid receptor binding localized in the dorsal horn of the spinal cord (Fig. IV-29).

Compared to systemically applied opioids, peridural opioids result in lesser side effects since the dose can be reduced. Administered at an interval every 12-15h, either morphine 3-5mg or buprenorphine 0.15-0.3mg diluted in 10-20ml of 0.9% saline are injected as a "single shot" peridural injection. By a using a motor-driven pump, continuous peridural (0.2mg/h of morphine or 0.018 mg/h of buprenorphine) opoid application, after a bolus application is possible. In neuropathic pain and in exercise-induced pain, the sole neuraxial application of an

Figure IV-29. Parts of the central nervous system, which show an accumulation of opioid binding sites. Note, opioid receptors are also located in the substantia gelatinosa of the spinal cord where neuraxial opioids exert their analgesic action via blockade of nociceptive afferents. Adapted from [88]

opioid often is insufficient. In such cases, the combined application of an opioid together with a local anesthetic, with the a2-agonist clonidine (20 ^g/h), or with the unspecific NMDA-antagonist like ketamine (0.1-0.5 mg/kg/day) significantly improves the attenuation of pain. For conversion from an oral to the intrathecal dose, on the first day of the neuroaxial application, 1/50 of the last daily oral opioid dose is administered while at the same time the oral dose is reduced by 50%. A neuroaxial dose (25%) is given initially, while the remaining quantity is infused over the whole day. Oral rescue medication should always be available where approximately 5% of the current total quantity of the opioid is given for breakthrough pain.

Preliminary clinical data suggest a pain-modulating effect of adenosine at the adenosine-A:-receptor at the spinal cord. Also, neostigmine when given in combination with an neuraxial opioid, has demonstrated a significant opioid-sparing effect, which is due to an increase of intrathecal acetylcholine concentration. Larger clinical studies with both compounds are still pending.

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