Development Of Tolerance During Longterm Use Of Opioids

Tolerance development during opioid ingestion is characterized by the need to continuously increase the dose for sufficient pain relief. The underlying cause is that the organism has adapted to the drug and in order to achieve the same effect (analgesia), higher doses have to be given. The majority of investigations, where opioids were given for tumor pain however made clear, that proportional to the duration of an opioid therapy there is no necessity for dose adjustment [65] and occasionally the dose could be reduced or in some cases even be completely omitted [10, 66]. Therefore opioids, once they are used solely for the purpose of suppressing intense pain, result in fewer incidence of tolerance development. Moreoften, a necessary dose increase in tumor patients is not due to tolerance development, but rather is based on a progression of the underlying disease, which corresponds with an increase in pain intensity. Development of tolerance to the opioid-related inhibition of motility of the intestine and to miosis, in contrast to the development of tolerance to opioid-induced analgesia, never develops. If, in the process of pain therapy, genuine tolerance becomes evident, it is likely to be due to an adjustment of the organism to a foreign substance. This is accompanied with the necessity to escalating doses in order to achieve sufficient analgesia, and may be due to several possibilities:

1. Psychosocial and environmental factors, whereby the development of tolerance can be regarded as the beginning of a dependency development.

2. A pharmacokinetic dependent mechanism, whereby an insufficient absorption in the intestinal tract, or an interaction with other compounds results in an insufficient plasma level.

3. Metabolic causes, whereby an increase in activity of specific liver enzymes result in an increase of metabolic degradation with a reduced concentration of the pharmacologically active compound. Due to the habituation of the organism to the opioid, an increased metabolic rate results in major degradation, which is mirrored in a loss of efficacy. Then the dose must be sequentially increased in order to achieve a continuous and sufficient analgesic effect.

4. Tolerance development at the cellular and molecular level. Several adaptation processes at the cellular level have to be discussed all of which result in a reduction of the analgesic effect:

- Desensitization of the receptor, which is due to a functional uncoupling of the receptor to its secondary intracellular mediator, the G-protein. Because phosphorilisation of the G-protein, a necessary step for mediation of effects is reduced, lesser amounts of protein kinases, especially the key-player PKC, are formed which results in lesser activation of ion-gated Ca++- and K+-channels. This process follows immediately within seconds after binding of a ligand to the specific ^-opioid receptor site.

- Internalization of the receptor into the cell, also termed endocytosis. In such instances the receptor sequesters into the cell, thereby not being available any more for additional binding which results in a lesser binding rate and a reduction in effects. Following internalization, the receptor again is recycled to the cell surface where it will be available for additional binding, a mechanism, which counteracts tolerance development. The process of internalization requires several minutes and it is important to note that internalization has been demonstrated for morphine and fentanyl while buprenorphine demonstrated rapid re-emergence at cell surface [21].

- Downregulation of the receptor is the key element in the cellular adaptation process to opioids resulting in long-term tolerance development. In this process the a-unit of the code G-protein in signal transmission is synthesized in lesser amounts by 6-Arrestin 2, resulting in a poorer transmission of all incoming signals. This process takes place within hours, and is most prominent during long-term application of potent opioids. Significance of 6-Arrestin 2 was documented by the fact that elimination of the appropriate gene resulted in a functional lack of 6-Arrestin 2 which was accompanied by a marked increase in analgesia and a significant extension in duration of action [67].

- Inhibition of gene expresson within the cell, the gene, which is responsible for the formation of new receptors (transcription) from protein molecules. This process is induced off within days during chronic intake of potent opioids.

- Increase of protein kinase C (PKC) activity. The key-player in intracellular phosphorylisation is PKC, which is activated via the second and intracellular mediator G-protein. PKC however in the long run also induces a compensatory activation of the excitatory N-methyl-D-aspartate (NMDA) receptor site. Due to activation of the NMDA-receptor there is an increase in transmembrane Ca2+-Ion transfer (Fig. IV-24) with an ensuing overresponsiveness to all incoming nociceptive afferents (antiopioid effect). Because opioids by themselves do not have any effect on an overactive NMDA-receptor,

Figure IV-24. The N-methyl-D-aspartate receptor being activated by the long-term use of opioids

additional nonspecific NMDA antagonists such as ketamine, dextromethor-phane or memantine have to be given in order to attenuate this hyperactivity of the excitatory receptor system. Alternatively, methadone can be given, since the opioid by itself has a small but measurable NMDA-antagonistic property.

Tolerance development can be regarded as a self-regulating mechanism of the organism trying to adjust to the new situation in order to achieve homeostasis. Because of this opioid-induced imbalance in pro- and anti-nociceptive activity the organism responds by an increased activation of pro-nociceptive transmitters (Fig. IV-25) related to substance P, cholecystokinin (CCK) and NMDA activation.

miri Analgesia Hyperalgesia Analgesia Hyperalgesia


miri Analgesia Hyperalgesia Analgesia Hyperalgesia


Figure IV-25. In order to balance the equation between pro- and anti-nociceptive transmission, the organism, during opioid ingestion, compensates this imbalance by activation of cholecystokinin (CCK), substance P (SP) and NMDA activation, resulting in tolerance development and the need for higher doses of an opioid. Adapted from [68]

Generally, tolerance development in the context of opioid therapy during chronic pain treatment:

• is more frequently observed in young than in elderly patients,

• is observed more often when short-acting opioids are used for pain therapy resulting in a so called. "roller coaster effect" with breakthrough pain. Therefore, once-a-day opioid intake is better than 4 times a day dosing,

• is particularly seen when opioids with a low intrinsic activity at the -receptor are used,

• is observed in individuals who take opioids when no pain is present,

• is likely to develop in patients who repeatedly and/or permanently need a rescue medication for sufficient pain attenuation,

• otherwise is a rare event, which however would be a desirable effect when it comes to respiratory depression, nausea, vomiting and hallucinations,

• more often is caused by a progression in the underlying disease and is not due to a reduced response of the receptor site to the ligand [69],

• usually is not to be expected when oral slow release opioid formulation is used to combat pain.


A recent large US interview-based study (n = 988) of both cancer and non-cancer patients revealed that a significant proportion of terminally ill patients prefer not to increase opioid analgesic doses to levels which effectively control their pain, primarily as a result of side effects such as constipation and confusion [70]. Constipation is frequently seen in up to 90% of all patients, particularly when opioids are needed in large quantities. The incidence of constipation, in contrast to the oral opioids, is much smaller when a transdermal therapeutic system such as fentanyl TTS (Duragesic®) or buprenorphine TDS (Butrans®) is used. For instance, in a controlled metaanalysis oral morphine slow release demonstrated a constipation rate of 48% while equianalgesic doses of transdermal fentanyl resulted in an incidence of up to 17% [71]. However, constipation still may present a problem during long term application. This common side effect is related to opioid receptor sites in the intramural plexus of the intestine, the first barrier between the exterior and the interior milieu. There the majority of the immune system (Payer plaques) are located (Fig. IV-26) and binding of opioids results in the inhibition of propulsion.

In order to overcome constipation, a bulk producing laxative and/or a fecal softener is recommended and should be given parallel with the prescription medication. If a regular laxative such as lactulose (Dupholac®) is insufficient, a more aggressive therapy must be initiated using a stimulant laxative such as bisacodyl (Dulcolax®), which acts directly at sensory parasympathetic nerve endings of the colonic mucosa. Since constipation sometimes results in a more difficult task than actual pain therapy [72], with the beginning of any long-term opioid medication for pain therapy a bulk-producing fiber-supplement laxative

Nerve Endings Opioid Receptors
Figure IV-26. The intestinal mucosa and the different muscle layers where opioids bind to specific receptor sites found in Auerbachs plexus

such as (Metamucil®) should be prescribed, a necessary adjunct to overcome the inhibition of gastrointestinal transit. In addition, a fecal sofetener (Colace®), a hyperosmolar glycerin agent (MiraLax®, Fleet®Glycerin), a bisacodyl containing preparation (Fleet Biscodyl®) or a mineral oil enema (Fleet Enema ®) can be considered as laxatives. Certain cases of constipation need to be treated more agressively using monobasic sodium phosphate (Fleet®Prep Kit). Presently two peripheral selective opioid antagonists (i.e. methylnaltrexone, alvimopan) are under clinical phase 2 evaluation, which are able to reverse morphine-induced prolongation of gastrointestinal transit without however, antagonising centrally mediated analgesia [73, 74].


These side effects are experienced by approximately 40%-60% of all patients, who take potent opioids for pain relief. In the majority of cases these side effects are based on a stimulation of the chemoreceptors in the area postrema of the chemore-ceptor trigger zone (CTZ), located within the medulla oblongata. To lesser extent they are due to a reduction in intestinal motility [10]. In general these side effects are only observed in the beginning of an opioid medication, they subside within the following days as there is the development of tolerance. Should nausea and emesis persist, neuroleptic agents such as metoclopramide (Reglan®), prochlorperazine

(Compazine®) or the more potent haloperidol (Haldol®) are agents of choice. The latter agent can be regarded as the most effective therapeutic intervention to overcome these phenomena. In addition, selective serotonin HT3-inhibitors, which selectively act at the CTZ site, such as ondansetron (Zofran®), dolasetron (Anzemet®) or even a selective A9-cannabinoid dronabinol (Marinol®) may be of benefit. Opioid-related nausea and emesis are seen mostly within the first 2-3 days with the start of medication, thereafter they subside as there is a development of tolerance and the additional medication can be stopped.


This is another opioid-related side effect, which has an incidence below 5%. It results in reduced vigilance and is a short-lived phenomenon, which subsides after the first days of medication. If, however, the opioid-related fatigue is pronounced, an additional central nervous stimulant such as methylphenidate extended release capsules (Ritalin® LA), dextroamphetamine extended release (Adderall® XR) or the wakefulness-promoting agent modafinil (Provigil®) should be prescribed.


Although this side effcet is transient in nature, it can be managed with an antihis-tamine such as diphenhydramine (Benadryl®) or a sedative (prometazine) as needed.

Constipation Prescription

Constipation Prescription

Did you ever think feeling angry and irritable could be a symptom of constipation? A horrible fullness and pressing sharp pains against the bladders can’t help but affect your mood. Sometimes you just want everyone to leave you alone and sleep to escape the pain. It is virtually impossible to be constipated and keep a sunny disposition. Follow the steps in this guide to alleviate constipation and lead a happier healthy life.

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