Opioids are efficacious and cost-effective analgesics, but tolerance limits their effectiveness. This paper does not present any new clinical or experimental data but demonstrates that there exist ascending sensory pathways that contain few opioid receptors. These pathways are located by brain PET scans and spinal cord autoradiography. These nonopioid ascending pathways include portions of the ventral spinal thalamic tract originating in Rexed layers VI–VIII, thalamocortical fibers that project to the primary somatosensory cortex (S1), and possibly a midline dorsal column visceral pathway. One hypothesis is that opioid tolerance and opioid-induced hyperalgesia may be caused by homeostatic upregulation during opioid exposure of nonopioid-dependent ascending pain pathways. Upregulation of sensory pathways is not a new concept and has been demonstrated in individuals impaired with deafness or blindness. A second hypothesis is that adjuvant nonopioid therapies may inhibit ascending nonopioid-dependent pathways and support the clinical observations that monotherapy with opioids usually fails. The uniqueness of opioid tolerance compared to tolerance associated with other central nervous system medications and lack of tolerance from excess hormone production is discussed. Experimental work that could prove or disprove the concepts as well as flaws in the concepts is discussed.
Chronic pain is one of the greatest causes of human suffering. Chronic pain becomes intractable when standard therapies fail to control the pain [
From the first-order afferent receptor (mechanical, thermal, or chemical) through the ascending tracts to the thalamo, reticular, and mesencephalic relays to the final destination in the somatosensory cortices, anterior cingulated gyrus, and basal ganglia, pain is associated with a net excitatory stimulus. Numerous studies and clinical observations, including those from neural blockade, cordotomy, or rhizotomy, support this concept [
Hemorrhagic destruction of the thalamus is associated with intractable pain (white arrow).
Destruction of posterior columns (arrow) from B 12 deficiency is associated with intractable pain. Subaute combined degeneration of
Opioid tolerance can be defined as a decrease in analgesic response with increasing dose or frequency of administration. Tolerance is the greatest obstacle to the development of effective opioid treatment for intractable pain. Tolerance to endogenous opioids is often rapid, whereas tolerance to exogenous opioids is often delayed [
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In vivo distribution of opioid receptors in human brain with decrease in receptors in area of S1 (arrow). Photo Researchers Picture Number: SF2688. Credit: Philippe Psaila/Photo Researchers, Inc. License: Rights Managed. Description: Opioid receptors. Colored sagittal Positron Emission Tomography. (PET) scan showing the normal distribution of opioid receptors in the human brain. By injecting a patient with an opioid tagged with carbon-11 (radioactive tracer), a color-coded scan is produced, showing the concentration of opioid receptors from red (highest) through yellow and green to blue (lowest).
Somatosensory cortex (S1) of parietal lobe (arrow). Schematic of cortical areas involved with pain processing and fMRI cropped.jpg From Wikipedia, the free encyclopedia.
Opioid receptors in thalamus (red) and secondary somatosensory cortex, S2 (arrow). Photo Researchers Picture Number: SF2687. Credit: Philippe Psaila/Photo Researchers, Inc. License: Rights Managed. Description: Opioid receptors. Colored frontal Positron Emission Tomography. (PET) scan showing the normal distribution of opioid receptors in the human brain. By injecting a patient with an opioid tagged with carbon-11 (radioactive tracer), a color-coded scan is produced, showing the concentration of opioid receptors from red (highest) through yellow and green to blue (lowest).
Secondary somatosensory cortex (S2) in green (arrow). Schematic of cortical areas involved with pain processing and fMRI cropped.jpg From Wikipedia, the free encyclopedia.
Sensory fibers of the thalamocortical tract project to the primary somatosensory cortex (S1) and secondary sensory cortex (S2) [
As shown in Figure
Ventral spinothalamic tract fibers (vst, white arrow) originate in non-opioid Rexed layers (VI–VIII) (dark arrow).
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Opioid-induced hyperalgesia is a condition that may occur after chronic administration of large doses of an opioid. It is characterized by a lowering of the pain threshold with an exaggerated response to painful and nonpainful stimuli [
The hypothesis that upregulation of non-opioid-dependent ascending sensory systems is a possible cause of opioid tolerance and opioid-induced hyperalgesia is novel, but recent reports have implied that this could be true [
Most pain practitioners acknowledge that opioid therapy in sufficient doses can ameliorate acute and chronic intractable pain, and addition of adjuvant medications such as antidepressants, anticonvulsants, and anti-inflammatory medication improves response. However, opioids alone cannot provide long-term relief because of tolerance, opioid-induced hyperalgesia, or side effects. Pain practitioners are also well aware that other nonopioid therapies, such as intravenous infusion of local anesthetics or ketamine, inhalation of nitrous oxide, or conduction block, provide reliable analgesia for patients suffering from intractable pain probably via a different mechanism than activation of opioid receptors.
If upregulation of non-opioid-dependent ascending nociceptive pathways is shown to be a cause of pain from opioid tolerance or opioid-induced hyperalgesia, providers may consider adding GABA agonist to the medication regime of opioid-tolerant patients. Interestingly, our patients who suffer from intractable pain have learned that alcohol and benzodiazepines, both indirect GABA agonists, provide additional, but unsafe, analgesia when combined with opioids. In addition to increasing GABA, decreasing glutamate or blocking glutamate receptors could possibly attenuate the excitatory activity of non-opioid-dependent pathways.
As espoused by most investigators, opioid tolerance is believed to be caused by ligand-receptor inefficiency [
Intractable pain is one of the leading causes of worldwide suffering. Opioids are the most consistent, efficacious, and cost-effective analgesics available. Tolerance to opioids limits their effectiveness, and some aspects of this phenomenon are unique to opioids when compared to other G-protein receptor ligand systems. One hypothesis of this paper is that some aspect of opioid tolerance is caused by homeostatic upregulation of non-opioid-mediated ascending nociceptive pathways, including the thalamocortical and ventral spinothalamic tracts and possibly the midline dorsal column tract. Another hypothesis is that upregulation of these tracts may contribute to opioid-induced hyperalgesia. As one observes in clinical practice, therapy with adjuvant agents combined with opioids, rather than opioids alone, produced the best outcome for the treatment of intractable pain. Aside from presumed stimulation of descending inhibitory tracts from some adjuvants, one possible explanation for these outcomes is that these therapies inhibit nonopioid ascending dependent tracts as well as opioid-dependent tracts. This paper offers a hypothetical explanation based on neuroanatomic correlation as to why adjuvants plus opioid therapy are most successful and single-opioid therapy usually fails. When shown a comparison of opioid and non-opioid ascending nociceptive dependent tracts, physicians and patients may develop a better understanding of their therapy.
The author has no conflict of interests to declare pertaining to the publication of this paper.
The author would like to thank Kathy Gage of Duke University for editorial assistance.