Coanalgesics Adjuvants For Longterm Pain Therapy With Opioids

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Co-analgesics are agents, which actually do not belong to the group of analgesics. In selective situations, however, they result in pain-modifying and opioid-additive/potentiating/opioid-sparing effects. In addition, co-analgesics are indicated whenever the pain is caused by a functional deficit in the descending pain-inhibitory pathways, or when basic suffering attains an important meaning for the patient. But most of all adjuvant therapy is related to the potential side effects of chronic opioid therapy (Table IV-4).

Co-analgesics, also termed adjuvants, rank as follows:

Corticosteroids - These non-selective co-analgesics have a major indication in case of nerve compression, cephalgia due to increased intracraniel pressure, spinal cord compression, bone metastases, plexus invasion, soft tissue swelling due to tumor invasion, lymphoedema, osteoarthritis and/or cartilage distruction. The general recommended agent is dexamethasone (Decadron®, Dexamethasone®) with an initial dose of 8-32 mg/day; followed by a slow reduction of the daily dose of up to 2-4 mg/day.

Table IV-4. Summary and incidence of possible side effects following pain therapy with an opioid (TCA=tricyclic antidepressant)

Side effect

Incidence (%)

Dose-dependent

Tolerance development

Therapy

Constipation

90-100

Yes

No

Laxatives

Nausea, emesis

20-40

No

5-7 days

Antiemetics

Sedation

2-10

Yes

3-4 days

Stimulants

Dizziness

2-5

Yes

No

Dose-reduction, opioid rotation

Hallucination

1-5

No

No

Haloperidol

Pruritus

1-5

No

Yes

Antihistamine

Urinary retention

0.5-1

No

No

Discontinuation TCAs

Antiepileptics - Their main indication is the lancinating-like spontaneous pain of neuropathic origin, which is seen in trigeminal neuralgia, post herpetic neuralgia, in tumor and phantom pain, as well as in pain of central origin (thalamic evoked pain following stroke). The most frequently used agent is carbamazepine (Tegretol®, Epitol®) or phenytoine sodium, which are given in combination with an opioid in doses of 800-1200 mg/day. Newer agents of the second generation of antiepileptics such as gabapentin, lamotrigine or topiramate often are used in pain of various origin and present an important part in the therapeutic armamentarium. Especially gabapentin (Neurontin®), due to its compatibility and few side-effects, has entered the core in pain therapy, whereby doses of up to 3200 mg/day can safely be administered.

Tricyclic antidepressants (TCA) - They are the mainstay in painful peripheral neuropathies, in pain with hyper-, dys-, or paresthesia and allodynia, which often are seen in diabetic patients, in herpetic neuralgia, and in tumor pain where nerve fibers are damaged or infiltrated by the underlying disease. The most frequently used compound of this class is amitriptyline (Elavil®, Enovil®), which induces a psychomotor sedation and increases the activity of the descending inhibitory nociceptive pathways. The initial dose amounts to 10-25 mg/day. When combining an opioid with amitriptyline, a single dose of 50-75 mg/day, because of its sedative properties, should be given before bedtime. Contrary, imipramine (Tofranil®, Janimine®), which also results in an increase in vigilance, the daily dose has to be given in the morning. The initial dose is 25-50 mg titrated to effect. When combined with an opioid, the dose should not exceed 50-100 mg/day. The rationale for use of an antidepressant is the fact that pain has its morphologic base in brain areas responsible for the emotional and the affective component of nociception, the limbic system. Apart, opioids also induce a euphoric-like feeling, which adds to the action of antidepressants. It is suggested that the antineuralgic properties of TCAs are independent of their antidepressant activity, and present research suggests that they activate the descending pain inhibitory system.

Neuroleptics and tranquilizer - Because chronic pain patients often present a jerky, provocative, and affect-unstable attitude with a disturbed sleep pattern while at the same time being tired and underpowered, sedative tranquilizers are often necessary to calm the patient down [7]. Based on their different profile in action, specific neuroleptic agents have to be chosen individually, using certain combinations in order to handle special psychological behavior patterns. Neuroleptics therefore are used in the context of a combination with an opioid, particularly when patients experience tumor-related pain. For combination of the opioid with a neuroleptic, haloperidol (Haldol®) 2-5 mg/day is recommended as this agent also prevents emesis. Although the nociceptive afferents are not affected, neuroleptics act indirectly by interfering at the nigrostriatal and the limbic system. Thus, they have an effect on the somatomotor and the emotional component of pain, resulting in tranquillization and an indifferent attitude. Especially, because of their potent antiemetic effect, neuroleptics present an important part in pain-related therapy with opioids (Table IV-5).

Contrary to pharmacological effects of neuroleptics at the monoaminergic, the serotoninergic, the noradrenergic, the dopaminergic and/or the cholinergic system, tranquilizers such as diazepam (Valium®, Diazepam®) or midazolam (Versed®) act at the g-amino butyric acid (GABA) receptor of the interneuronal inhibitory system of the spinal cord. By increasing interneuronal activity at the endorphinergic system, the analgesic effect of opioids is potentiated. At the same time the pain-mediating excitatory neurotransmitters such as glutamate and substance P, are inhibited particularly in the dorsal horn of the spinal cord [7]. While antidepressants activate the descending pain-inhbitory serotinergic and noradrenergic pathways via activation at the dorsal horn of the spinal cord, neuroleptics act as antagonists at the dopamine receptor, and potentiate tricyclic antidepressants indirectly (Fig. IV-5).

Laxatives - Parallel with any long-term administration of an opioid, control of constipation is mandatory (Table IV-4). Therefore, regular intake of a laxative like a stool softener (Docusate sodium), lactulose (Dupholax®), Sennosid B, bisacodyl (Dulcolax®) or sodium-picosulfate (Laxoberal®) is mandatory. Such co-medication

Table IV-5. Adjuvant therapy using TCAs in chronic pain treatment with different modes of action

Neuroleptics

Anxiolytics, antipsychotics

Pain with anxiety disorders

Desipramine

Zolpidem

Levopromazine

Buspirone

Haloperidol

Fluphenazine

Promethazine

Doxepin

Prochlorperazine

Amitriptyline

Pain with depressive disorders

Fluoxitine

Imipramine

Fluphenazine

Mianserine

Trazodone

Trimipramine

Thioridazine

Maprotiline

Paroxetine

Melitracen

Respiratory Depression

Clonidine

Inhibititory Synapse

Excitatory Synapse

Clonidine

Inhibititory Synapse

Local

Interneuron

Enkephaline

GABA

Glycine

Dopamine

Somatostatin

descending Interneuron Serotonin Norepinephrine

Excitatory Synapse

Glutamate Substance P CCk

Neurotensin Somatostatin

Figure IV-5. Schematic representation of the transmitter systems and agents involved the propagation and procession of pain impulses in the dorsal horn of the spinal cord, resulting in either both inhibition or potentiation of nociceptive afferents via neurotransmitter release (GABA = ^-aminobutyric acid; CCK = cholecystokinine; CGRP = calcitonine gene-related peptide; ENK = enkephalin)

should accompany each opioid, since opioid-related constipation may become a severe obstacle in opioid therapy, which may even become more difficult than the actual pain therapy. In cases with conventional resistent constipation, two selective peripheral opioid-antagonists, i.e., methylnaltrexone (0.1-0.3 mg/kg s.c.) [8] and alvimopan (6mg oral) [8, 9] available. Since both agents do not penetrate the blood-brain barrier, centrally-mediated analgesia is preserved.

Antiemetics - When opioids induce nausea and/or emesis, administration of an antiemetic is indicated. For such purposes one should start with metoclo-pramide (Reglan®) and then change to more potent ones: the neuroleptic haloperidol (Haldol®) or domperidone (Motilium®), which act via dopamine-receptors in the chemoreceptor trigger zone (CTZ) within the medulla. Aside from a neuroleptic, a selective serotonine subreceptor inhibitor, which acts directly at the 5-HT3 (5-hydroxytryptamine) binding site located in the chemoreceptor trigger zone (CTZ), ondansetron (Zofran®) should be considered. Since opioid-related nausea and emesis, because of tolerance development, are rather short-lived phenomena, the need for antiemetics is only within the first days in the opioid-naive patient.

Analeptics - Sufficient pain therapy with central acting opioids often results in marked sedation. While this is seen predominantly with the start of opioid therapy, this side effect is characterized by the development of tolerance in the later period. If, however, side effects persists and if a dose reduction does not lead to desired reduction, analeptics such as caffeine, methylphenidate (Ritalin®), pemoline (Cylert®), dextroamphetamine (Dexedrine®) or modafinil (Provigil®) are indicated, resulting in an increase of vigilance.

Sodium channel blockers - Especially in nerve injury with ongoing ectopic activity and possible cross talk to spared nerves neuropathic pain develops. In such instances Na+-channel blockers may be advantageous since they reduce the spontaneous ongoing activity which is perceived as continuing pain, resulting in central hyperexcitability and upregulation of voltage dependent Ca++ -channels within the spinal cord. Because there is loss of inhibitory interneurons (e.g. GABA), mexiletine (Mexitil®) or local anesthetics such as bupivacaine (Marcaine®, Sensorcaine®) or lidocaine (Xylocaine®, Lidocaine®) present attractive adjuvants, because spontaneous discharge in injured nerves and hyperactive collateral fibers is reduced.

Buprenorphine - Opioid with Unique Receptor Kinetics for Chronic Pain

Different opioids used in the therapy of chronic pain demonstrate a preference of binding to a different receptor population, which results in distinct pharmaco-dynamic effects, but also in the incidence of side effects (Table IV-6). In this regard buprenorphine (Buprenex®, Transtec®), due to its specific interaction with

Table IV-6. Summary of

co-analgesics in chronic tumor-related pain therapy

Type of pain

Co-analgesics

Alternative therapy

Bone metastasis or

NSAIDs, steroids biphosponate

Local radiotherapy, radionucleoids

infiltration

agents

Nerve compression,

Cortocosteroids, antiepileptics,

Radiotherapy,

infiltration

neuroleptics, antidepressants

neurolytic-sympathetic block

Increased intracranial

Corticosteroids, diuretics,

Radiotherapy, head up positioning

pressure

antiepileptics

Lymphoedema

Corticosteroids, diuretics

Sympathetic block, compression,

lymph drainage

Muscle spasms, soft

Corticosteroids, NSAIDs, centrally

Physiotherapy, therapeutic local

tissue infiltration

acting muscle relaxants

blocks, relaxation therapy

Distention pain

Corticosteroids

Radiotherapy, neurolytic block of

(liver, spleen)

coeliac plexus,

Bone related

Biphosphonate agents (Clodronate,

Radionucleotides

metastatic disorders

Etodronate, Palmidronate)

Antiepileptics,

Postherpetic

Antiepileptics

Sympatholysis, lidocaine patch 5%

neuralgia

Par-, dysesthesia

Antidepressants, neuroleptics,

Local anesthetic agents

Muscle spasticity

baclofen

NMDA-antagonists, gabapentin

Adapted from [10]

Adapted from [10]

the opioid receptor site and contrary to the other opioids, is characterized by the following features:

1. It has a very slow association rate to the receptor site, which clinically results in a slow onset of action. Thus it can be expected that maximum efficacy is seen after 60 min.

2. Once having bound to the receptor site, binding is very intense which results in little or no displacement by other opioids.

3. Buprenorphine shows high affinity to the receptor site. This is of advantage in the clinical setting as small dosages already result in marked conformational changes of the serpentine loops (Fig. IV-6), resulting in an intense analgesic effect.

4. Buprenorphine exhibits a slow dissociation from the receptor site, which clinically results in a long duration of action.

5. Because of its high potency lesser opioid receptors have to be occupied in order to achieve a sufficient analgesic affect. Thus, there is a sufficient receptor reserve, which clinically can be used for the co-administration of or the switch to another opioid.

Due to the unique receptor kinetics, use of buprenorphine in general practice is characterized by the following features:

1. A long onset of action. When using a sublingual tablet, 60 min may elapse until the drug shows maximal analgesic effect, and after intravenous administration a time span of 30 min has to be expected until the patient achieves total pain relief.

Suboxone Receptor Binding
Figure IV-6. The opioid ^-receptor with the typical seven transmembrane serpentine loops, the site of binding of buprenorphine

Because of this apparent time lag, one has to wait before administering a second dose of the opioid. In particular, early repetitive doses of buprenorphine should be avoided in the elderly as this may result in respiratory depression -receptor interaction!).

2. Because binding of buprenorphine to the opioid receptor is very intense, pure antagonists in doses higher than usually administered are necessary to displace the ligand from its receptor site [11]. If, however, respiratory depression gets to a clinical relevant degree, it can be antagonized by repetitive and higher doses of the potent antagonist naloxone (sometimes up to 10 mg of naloxone). When starting antagonism, the intravenous dose of naloxone should be titrated against vital parameters such as respiratory rate, blood pressure and behavior pattern. In order to avoid an acute abstinence syndrome, a starting dosage of 0.4-0.8 mg is given, followed by tapering up to 2.0 mg. Because of the short half-life of naloxone, an infusion of 5 mg/h should be administered in the following 24 h accompanied by the simultaneous surveillance in an intensive care environment. Such precautions are necessary in order to prevent a reoccupation of the receptors by buprenorphine [12], which otherwise would result in a late re-occurence of respiratory depression. Another specific opioid antagonist, nalmefene (Revex®) seems to be a more favorable agent for antagonists, because it has a higher receptor specificity and affinity, which results in a longer half-life than naloxone [12]. As an alternative, the nonspecific analeptic agent doxapram (Dopram®) can be used in order to reverse respiratory depression via stimulation of pressor receptors in the glomus caroticus. Such practice has the advantage that the analgesic effect of buprenorphine is not antagonized while at the same time reversing the depressed respiratory drive.

Because of the respiratory depressive ceiling effect of buprenorphine, a clinical relevant impairment of respiration is rarely seen in patients while this often is due to the co-administration of a sedative or a hypnotic.

3. The intensive and long receptor binding results in a long duration of the analgesic effect. Besides controlled release morphine (MS-Contin®) or controlled release oxycodone (OxyContin®), it has the longest duration of action among opioids being used in medicine [13]. Therefore repetition may only be necessary every 8-9 h, which in chronic pain patients is advantageous. By using the new transdermal matrix technology of buprenorphine (BuTrans®), duration of analgesia may even be prolonged further up to 96 h, resulting in more comfort for and compliance by the patient.

4. The slow dissociation rate of buprenorphine from the receptor site results in limited physical dependency and a lesser likelihood in the development of tachy-phylaxis. Since tachyphylaxis is accompanied by the necessity to increase the dose in order to achieve a similar effect, long-term administration of this opioid over weeks and months is characterized by little or no tolerance development. Tolerance development to an opioid is due to a decrease in binding affinity of the ligand to the receptor, it has been termed as "down-regulation" [14]. In addition long-term application is also linked to sequestration of receptors into the cell also termed internalization. Such an effect can be seen with morphine and fentanyl while buprenorphine, due to its partial ^-agonistic potency does not show such a characteristic, since receptors demonstrate rapid re-emergence at cell surface [21] .

5. Because of the high affinity of buprenorphine at the receptor site, small doses (0.3-0.6 mg/70 kg i.v.) already induce a sufficient deep analgesic effect.

6. Also, because of the high affinity to the binding site and its potency (40x morphine) only a small number of receptors need to be occupied for mediating a sufficient analgesic effect. Such a characteristic has the advantage that pain relief can be increased by the additional application of a fast release buccal buprenorphine or by a morphine fast release tablet. Such a strategy is only possible through unbound, available receptor sites, termed receptor reserve, which enables additional binding (Fig. IV-7).

7. Since only a small number of receptors have to be occupied in order to induce a potent analgesic effect, opioid rotation from buprenorphine to oral extended release morphine or vice versa, is possible. Due to this receptor reserve (fig. IV-8) a change from one opioid to another, such as slow release oxycodone, hydromor-phone or morphine, can be performed without any problem, whereby equianal-gesic doses should be used [15]. Transformation is accomplished by multiplying the total daily buprenorphine dose by 70, thus receiving the total appropriate daily dose of morphine, which is distributed over 24 h, necessary for a sufficient blockade of nociceptive afferents with no gap in pain therapy [10].

8. The putative analgesic ceiling effect of buprenorphine so far has only been demonstrated in the animal when using extremely high doses, which clinically are above the therapeutic range [17] (Fig. IV-9).

9. In the clinical setting use of therapeutic doses of up to 10mg/day, buprenorphine behaves like a pure ^-type ligand and no analgesic ceiling effect can

What Respiratory Depression
Figure IV-7. Proportional occupation of receptors by buprenorphine and morphine. Because of such receptor reserve, a switch from buprenorphine to morphine is possible as a sufficient number of non-occupied receptors are available for additional binding
Buprenorphine Ceiling Effect

Figure IV-8. As demonstrated in PET scan studies, complete occupation of all binding sites with buprenorphine is only accomplished by very high doses of the agent >16mg [16]. In pain patients, lower dosages are commonly used and buprenorphine behaves like a full agonist, resulting in available receptors sites for binding with another opioid be demonstrated [19]. Contrary to other potent opioids, however, there is a respiratory ceiling as demonstrated in human volunteers (Fig. IV-10). 10. Because of its high affinity, buprenorphine has a wide therapeutic margin of safety (LD50/ED50), which results in little or no cardiovascular depression

Analgesic Ceilings

Figure IV-9. Analgesic ceiling-effect of buprenoprhine when compared to morphine in the animal using the shock titration test. Adapted from [18]

Tramadol Hypotension Mechanism
Figure IV-10. Contrary to fentanyl there is a respiratory ceiling-effect following increasing doses of buprenorphine. Adapted from [20]

(Fig. IV-11). Even inadvertent overdose, except respiratory depression, results in no negative side effects such as marked hypotension or a depression of myocardial contractility. 11. For signal transduction buprenorphine interacts with a subset of the intracellular transmitter system, the G-protein (Fig. IV-12). It is because of this difference in

Buprenorphine

Sufentanil

Fentanyl

Atfentanit

Butorphanol

Morphine

Pethidine

Pentazocine Tramadol

□ □

I ; i i i i 0 2 4 6 8 10 Therapeutic margin of safety (Inx)

Figure IV-11. The therapeutic margin of safety (LD50/ED50) of different opioid ligands

Figure IV-11. The therapeutic margin of safety (LD50/ED50) of different opioid ligands

Respiratory Depression

Figure IV-12. Following drug binding at the cell surface the message is conveyed intracelluarly via the G-protein. Contrary to other opioids a subset of G-proteins is activated by buprenorphine. Adapted from [21]

the mode of action, that a low incidence in tolerance development is observed. This is in contrast to other pure agonists such as morphine or fentanyl, where long-term application for chronic pain treatment often results in the gradual increase of the necessary dose. 12. Compared to other opioids buprenorphine exhibits a simultaneous K-antagonistic effect (Table IV-7). Because of this feature the ligand demonstrates a lesser incidence of dysphoria, especially when given in higher doses.

Table IV-7. Receptor interaction of different opioids and their prototype ligands used in chronic pain therapy

Opioid

Agonistic activity

Antagonistic activity

Pure ^-type agonist,

K, 8

None

e.g. morphine

Pure antagonist,

None

|, K, 8

e.g. naloxone

Mixed agonist/antagonist

K

I, 8

e.g. nalbuphine

Partial agonist,

I

K

e.g. buprenorphine

Adapted from [22]

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