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. 1. Introduction Chronic pain is one of the greatest causes of human suffering. Chronic pain becomes intractable when standard therapies fail to control the pain [1, 2]. In many societies and regulated by laws, chronic opioid therapy is reserved for patients who suffer from intractable pain [3, 4]. Common examples of diseases that lead to intractable pain include arachnoiditis, brachial plexus avulsion, thalamic syndrome, and multiple surgical traumas. Patients who suffer from these conditions are frequently referred to pain management physicians who may consider invasive therapies such as neurosurgical deafferentation, peripheral, spinal cord, or deep brain stimulation, or high-dose opioid therapy [5]. This paper discusses possible mechanisms of two problems of chronic opioid therapy, namely, tolerance and opioid-induced hyperalgesia. 2. Pain Is an Excitatory Process, and Opioids Are Inhibitory [6, 7] 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
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