Opioids, sensory systems and chronic pain

European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Review

Opioids, sensory systems and chronic pain Christoph Stein n Department of Anesthesiology and Critical Care Medicine, Freie Universität Berlin, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany

art ic l e i nf o

a b s t r a c t

Keywords: Morphine Inflammation Arthritis Dorsal root ganglion Peripheral Chonic pain Non-malignant pain Cancer pain Surgery Postoperative pain Dependence Addiction Tolerance Clinical applications

Opioids are the oldest and most potent drugs for the treatment of severe pain. Their clinical application is undisputed in acute pain (e.g. associated with trauma or surgery) but their long-term use in chronic pain has met increasing scrutiny. Therefore, this article will review sensory mechanisms related to opioid analgesia and side effects with a special emphasis on chronic pain. Central and peripheral sites of analgesic actions and side effects, as well as conventional and novel opioid compounds will be discussed. Since pain is a complex bio-psycho-social phenomenon, non-pharmacological considerations important for the understanding of opioid analgesic efficacy are also included. Finally, examples of challenging clinical situations such as the perioperative management of patients receiving long-term opioid treatment are illustrated. & 2013 Elsevier B.V. All rights reserved.

Contents 1.

Chronic pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1. Basic concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1.1. Excitatory mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.1.2. Inhibitory mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.1.3. Translation of basic research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2. Clinical concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2.1. Definitions and prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2.2. Bio-psycho-social concept and multidisciplinary management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2. Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1. Opioid receptors and opioid peptides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2. Opioid drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.3. Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.4. Hyperalgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.5. Central and peripheral sites of action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.6. Opioid receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3. Clinical problems associated with opioid use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.1. Dependence and addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.2. Acute pain management in the chronic pain patient. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 3.3. Long-term opioid use in chronic non-malignant pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

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1. Chronic pain 1.1. Basic concepts 1.1.1. Excitatory mechanisms Pain may be roughly divided into two broad categories: physiological and pathological pain. Physiological (acute, nociceptive) pain is an essential early warning sign that usually elicits reflex withdrawal and thereby promotes survival by protecting the organism from (further) injury. In contrast, pathological (e.g. neuropathic) pain is an expression of the maladaptive operation of the nervous system; it is pain as a disease (Woolf, 2004). Physiological pain is mediated by a sensory system consisting of primary afferent neurons, spinal interneurons and ascending tracts, and several supraspinal areas. Trigeminal and dorsal root ganglia (DRG) give rise to high-threshold Aδ- and C-fibers innervating peripheral tissues (skin, muscles, joints, viscera). These specialized primary afferent neurons, also called nociceptors, transduce noxious stimuli into action potentials and conduct them to the dorsal horn of the spinal cord (Fig. 1). When peripheral tissue is damaged, primary afferent neurons are sensitized and/or directly activated by a variety of thermal, mechanical and/or chemical stimuli. Examples are protons, sympathetic amines, adenosine triphosphate (ATP), glutamate, neuropeptides (calcitonin gene-related peptide, substance P), nerve growth factor, prostanoids, bradykinin, proinflammatory cytokines and/or chemokines (Rittner et al., 2008; Stein, 2012; Woolf and Ma, 2007). Many of these agents lead to opening (gating) of cation channels in the neuronal membrane. Such channels include the capsaicin-, proton- and heat-sensitive transient-receptor-potentialvanilloid-1 (TRPV1), or the ATP-gated purinergic P2X3 receptor. This gating produces an inward current of Na þ and Caþþ ions into the peripheral nociceptor terminal. If this depolarizing current is sufficient to activate voltage-gated Na þ channels (e.g. Nav1.8), they too will open, further depolarizing the membrane and initiating a burst of action potentials that are then conducted along the sensory axon to the dorsal horn of the spinal cord (Wood, 2007; Woolf and Ma, 2007). Thereafter these impulses are transmitted to spinal neurons, brainstem, thalamus and cortex (Schaible, 2007; Tracey and Mantyh, 2007).

anterior anteriorcingulate cingulate cortex, insula, cortex (ACC) insula prefrontal cortex prefrontal cortex

somatosensory cortical areas cortex SI, SI,SII SIIin

somatosensory cortex

medial thalamus lateral thalamus

peripheral tissue

medial spinothalamic tract lateral

C-fiber C fibre

Aδ fibre Aδ-fiber sympathetic axon motoaxon motor axon Fig. 1. Nociceptive pathways, adapted from Brack et al. (2006). For details see text.

Transmission of input from nociceptors to spinal neurons that project to the brain is mediated by direct monosynaptic contact or through multiple excitatory or inhibitory interneurons. The central terminals of nociceptors contain excitatory transmitters such as glutamate, substance P and neurotrophic factors. These activate postsynaptic N-methyl-D-aspartate (NMDA), neurokinin (NK1) and tyrosine kinase receptors, respectively. Repeated nociceptor stimulation can sensitize both peripheral and central neurons (activity-dependent plasticity). In spinal neurons such a progressive increase of output in response to persistent nociceptor excitation has been termed “wind-up”. Later, sensitization can be sustained by transcriptional changes in the expression of genes coding for various neuropeptides, transmitters, ion channels, receptors and signaling molecules (transcription-dependent plasticity) in both nociceptors and spinal neurons. Important examples include the NMDA receptor, cyclooxygenase-2 (COX-2), Caþþ and Na þ channels, cytokines and chemokines expressed by neurons and/or glial cells (Basbaum et al., 2009). In addition, physical rearrangement of neuronal circuits by apoptosis, nerve growth and sprouting occurs in the peripheral and central nervous system (Schaible, 2007; Woolf, 2004).

1.1.2. Inhibitory mechanisms Concurrent with the events described above, powerful endogenous mechanisms counteracting pain unfold both in the periphery and in the central nervous system. In injured tissue this occurs by interactions between leukocyte-derived opioid peptides and peripheral nociceptor terminals carrying opioid receptors (Stein et al., 1990, 2003; Stein and Machelska, 2011) and/or by antiinflammatory cytokines (Rittner et al., 2008). Inflammation of peripheral tissue leads to increased expression, axonal transport and enhanced G-protein coupling of opioid receptors in DRG neurons as well as enhanced permeability of the perineurium. These phenomena are dependent on sensory neuron electrical activity, production of proinflammatory mediators, and the presence of nerve growth factor within the inflamed tissue (Cayla et al., 2012; Mousa et al., 2007a; Rittner et al., 2009b; Stein, 2012; Stein and Machelska, 2011). In parallel, opioid peptide-containing immune cells extravasate and accumulate in the inflamed tissue. These cells upregulate the gene expression of opioid peptide precursors and the enzymatic machinery for their processing into functionally active peptides (Busch-Dienstfertig et al., 2012; Mousa et al., 2004; Sitte et al., 2007). In response to stress, catecholamines, corticotropin releasing factor, cytokines, chemokines or bacteria, leukocytes secrete opioids, which then activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of nociceptors, the release of excitatory neuropeptides, or both (Rittner et al., 2009a; Stein and Machelska, 2011) (Fig. 2). The clinical relevance of these mechanisms has been shown in studies demonstrating that patients with knee joint inflammation express opioid peptides in immune cells and opioid receptors on sensory nerve terminals within synovial tissue (Mousa et al., 2007b; Stein et al., 1993). After knee surgery pain and analgesic consumption was enhanced by blocking the interaction between the endogenous opioids and their receptors with intraarticular naloxone or adrenergic antagonists (Kager et al., 2011; Stein et al., 1993), and was diminished by stimulating opioid secretion (Likar et al., 2007). In the spinal cord, inhibition is mediated by the release of opioids, GABA or glycine from interneurons, which activate presynaptic opioid- and/or GABA-receptors on central nociceptor terminals to reduce excitatory transmitter release. In addition, the opening of postsynaptic K þ or Cl− channels by opioids or GABA, respectively, evokes hyperpolarizing inhibitory potentials in dorsal horn neurons. During ongoing nociceptive stimulation spinal interneurons upregulate gene expression and production

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Fig. 2. Endogenous antinociceptive mechanisms within peripheral injured tissue, adapted from Stein and Machelska (2011). Opioid peptide-containing circulating leukocytes extravasate upon activation of adhesion molecules and chemotaxis by chemokines. Subsequently, these leukocytes are stimulated by stress or releasing agents to secrete opioid peptides. For example, corticotropin-releasing factor (CRF), interleukin-1β (IL-1) and noradrenaline (NA, released from postganglionic sympathetic neurons) can elicit opioid release by activating their respective CRF receptors (CRFR), IL-1 receptors (IL-1R) and adrenergic receptors (AR) on leukocytes. Exogenous opioids (EO) or endogenous opioid peptides (OP, green triangles) bind to opioid receptors (OR) that are synthesized in dorsal root ganglia and transported along intraaxonal microtubules to peripheral (and central) terminals of sensory neurons. The subsequent inhibition of ion channels (e.g. TRPV1, Caþþ) (see Fig. 3 and text) and of substance P (sP) release results in antinociceptive effects.

of opioid peptides (Cheng et al., 2002; Herz et al., 1989). Powerful descending inhibitory pathways from the brainstem also become active by operating mostly through noradrenergic, serotonergic and opioid systems. A key region is the periaqueductal grey. It projects to the rostral ventromedial medulla, which then projects along the dorsolateral funiculus to the dorsal horn (Millan, 2002). The supraspinal integration of signals from excitatory and inhibitory neurotransmitters, cognitive, emotional and environmental factors eventually results in the central perception of pain. When the intricate balance between biological, psychological and social factors becomes disturbed, chronic pain can develop.

pain relief or opioid use in patients (Lee et al., 2012). Neuroimaging can only detect alterations associated with nociceptive processes whereas clinical pain encompasses a much more complex subjective experience that critically relies on self-evaluation. Thus, imaging cannot provide an objective proxy, biomarker or predictor for pain (Davis et al., 2012). Genetics of pain is another budding scientific field. However, although basic research has produced some evidence for a genetic control of pain, such findings are not expected to serve as a guide to individualized (“personalized”) clinical pain therapy any time soon (Mogil et al., 2010; Roberts et al., 2012). 1.2. Clinical concepts

1.1.3. Translation of basic research Basic research on pain continues at a rapid pace but translation into clinical applications has been difficult (Whiteside et al., 2008; Woolf, 2010). Many obstacles have been discussed, including overinterpretation of data, reporting bias towards neglecting negative results, and flawed design of experimental and clinical studies (Berge, 2011; Woolf, 2010). Animal studies are indispensable, continue to be improved, and have successfully predicted adverse side effects of drug candidates (Berge, 2011; Whiteside et al., 2008). However, for ethical reasons many models are restricted to days or weeks, while human chronic pain can last for months or years. Therefore, animal models do not mirror the truly chronic clinical situation and should be more cautiously termed as reflecting “persistent pain” (Berge, 2011; Mogil et al., 2010; Whiteside et al., 2008). Brain imaging is an area of intense research and numerous studies have investigated changes in patients with various pain syndromes. However, such studies have not yet provided reproducible findings specific for a disease or a pathophysiological basis for individual syndromes (Mogil et al., 2010). Similarly, imaging opioid mechanisms in the human brain has been limited mostly to single dose studies in healthy volunteers and has not substantially advanced our understanding of

1.2.1. Definitions and prevalence The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (Loeser and Treede, 2008). This classification further states that pain is always subjective and that it is a sensation in parts of the body. At the same time it is unpleasant and therefore also an emotional experience. Aside from malignant disease, many people report pain in the absence of tissue damage or any likely pathophysiological cause. There is usually no way to distinguish their experience from that due to tissue damage. Nociception is neurophysiological activity in peripheral sensory neurons (nociceptors) and higher nociceptive pathways and is defined by the IASP as the “neural process of encoding noxious stimuli”. Nociception is not synonymous to pain. Pain is always a psychological state, even though it often has a proximate physical cause. Chronic pain is defined as “pain without apparent biological value that has persisted beyond the normal tissue healing time” or as “extending in duration beyond the expected temporal boundary of tissue injury and normal healing, and adversely affecting the function or well-being of the individual” (American Society of Anesthesiologists, 2010). The presence or extent of chronic pain often does not correlate with the documented tissue pathology.

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Beyond these general definitions there exists no common understanding about the characteristics of the chronic pain patient. This may be one reason why estimates of pain prevalence differ greatly from one publication to another. Heterogeneous populations, the occurrence of undetected comorbidity, different definitions of chronic pain and different approaches to data collection have resulted in estimates from 20 to 60%. Some surveys indicate a higher prevalence among women and the elderly. Chronic pain has enormous socio-economic costs. In the United States alone, annual expenditures amount to over 600 billion $ for healthcare, disability compensation, lost workdays and related expenses. Comparable figures have been reported by other countries (Langley, 2011; Pizzo and Clark, 2012). There is a tradition to distinguish between malignant (related to cancer and its treatment) and non-malignant (e.g. neuropathic, musculoskeletal, inflammatory) chronic pain. Little evidence exists to suggest that different somatic or psychological mechanisms warrant such a distinction. Non-malignant chronic pain is frequently classified into inflammatory (e.g. arthritic), musculoskeletal (e.g. low back pain), headaches and neuropathic pain (e.g. postherpetic neuralgia, phantom pain, complex regional pain syndrome, diabetic neuropathy, HIV neuropathy). Lead symptoms of neuropathic pain include spontaneous lancinating, shooting or burning pain, hyperalgesia and/or allodynia (Baron, 2006). Cancer pain can originate from invasion of the tumor into tissues innervated by primary afferent neurons (e.g. pleura, peritoneum) or directly into peripheral nerve plexus. In the latter, neuropathic symptoms may be predominant. Pain is often underestimated by medical staff and family members, resulting in poor pain control (Pizzo and Clark, 2012). Many treatments for cancer are associated with severe pain. For example, cytoreductive radio- or chemotherapy frequently causes painful oral mucositis, especially in patients with bone marrow transplantation (Barasch and Peterson, 2003).

1.2.2. Bio-psycho-social concept and multidisciplinary management Cancer and non-cancer patients with chronic pain have in common the complex influences of biological (tissue damage), cognitive (memory, expectations), emotional (anxiety, depression) and environmental factors (reinforcement, conditioning). Many patients present with limited mobility, lack of motivation, depression, anger, anxiety and fear of reinjury, which hamper the return to normal work, social or recreational activities. Pain behaviors such as limping, medication intake, or avoidance of activity are all subject to operant conditioning, i.e. they respond to reward and punishment. For example, pain behaviors may be positively reinforced by attention from a spouse or healthcare provider (e. g. by inadequate use of medications). Conversely, such behaviors can be extinguished when they are disregarded or when incremental activity is reinforced by social attention and praise (Fordyce et al., 1968). The interplay between biological, psychological and social factors results in the persistence of pain and illness behaviors (Flor and Diers, 2007; Fordyce et al., 1968). Treating only one aspect of this complex syndrome is obviously insufficient. Therefore, a bio-psycho-social concept of pain has been adopted. However, its implementation into daily practice has been tardy, especially concerning chronic pain patients (Gatchel and Okifuji, 2006; Schatman, 2011). With the help of this concept it is possible to understand why chronic pain may exist without obvious physical cause. Interestingly, recent studies showed that the experience and regulation of social and physical pain may share a common neuroanatomical basis (Eisenberger et al., 2003). In a multimodal approach, pain management addresses physical, psychological and social skills and underscores the patients’ active responsibility to regain control over life by improving function and well-being (Flor and Diers, 2007; Jacobson et al., 1997). This

encompasses various pharmacological and non-pharmacological (psychological, physiotherapeutic) treatment strategies (Stein and Kopf, 2013). Meta-analyses have shown that multidisciplinary programs offer the most efficacious and cost-effective evidence-based treatment for chronic non-malignant pain (Gatchel and Okifuji, 2006). Treatment of chronic pain without an interdisciplinary approach is inadequate and can lead to misdiagnoses (Engel et al., 1996; Gatchel and Okifuji, 2006; Jacobson et al., 1997). However, many patients expect complete resolution of pain and return to full function, a goal that may not be achievable. In many cases realistic options are partial reduction of pain, improvement of physical function, mood and sleep, development of active coping skills, and the return to work. Thus, rehabilitation rather than cure is the most appropriate therapeutic option (Gatchel and Okifuji, 2006) and individual motivation is an important factor determining how well patients learn to manage pain (Jensen et al., 2003). One component of pain therapy is the use of analgesic drugs. Such compounds interfere with the generation and/or transmission of impulses following noxious stimulation in the nervous system (nociception). This can occur at peripheral and/or central levels of the neuraxis. The therapeutic aim is to diminish the perception of pain. Analgesics aim at modulating either the formation of noxious chemicals (e.g. prostaglandins) or the activation of neuronal receptors/ion channels transducing/transmitting noxious stimuli (e.g. peptide-, kinin-, monoamine-receptors, Na þ channels). Drugs currently used in chronic pain include opioids, non-steroidal anti-inflammatory drugs (NSAIDs), serotonergic compounds, antiepileptics and antidepressants (Stein and Kopf, 2013). Mixed drugs combine different mechanisms, for example noradrenaline reuptake inhibition and opioid agonist effects (tramadol, tapentadol), or opioid agonist and NMDA antagonist effects (ketamine). In addition, placebo treatments have shown impressive analgesic effects, mediated by opioid and nonopioid mechanisms (Carlino et al., 2011)

2. Opioids 2.1. Opioid receptors and opioid peptides Opioids act on heptahelical G-protein-coupled receptors. Three types of opioid receptors (μ, δ, κ) have been cloned and their crystal structures have been resolved (Filizola and Devi, 2012). Several subtypes, possibly resulting from gene polymorphisms, splice variants or alternative processing have been proposed. Opioid receptors are localized and can be activated along all levels of the neuraxis including peripheral and central processes of primary sensory neurons (nociceptors), spinal cord (interneurons, projection neurons), brainstem, midbrain and cortex. All opioid receptors couple to G-proteins (mainly Gi/Go) and subsequently inhibit adenylyl cyclase, decrease the conductance of voltagegated Caþþ channels and/or open rectifying K þ channels (Fig. 3a). These effects ultimately result in decreased neuronal activity (Zöllner and Stein, 2007). The prevention of Caþþ influx inhibits the release of excitatory (pronociceptive) neurotransmitters. A prominent example is the suppression of substance P release from primary sensory neurons, both within the spinal cord and from their peripheral terminals within injured tissue. At the postsynaptic membrane, opioids produce hyperpolarization by opening K þ channels, thereby preventing excitation or propagation of action potentials in second order projection neurons. In addition, opioids inhibit sensory neuron-specific tetrodotoxinresistant Na þ channels, TRPV1 channels and excitatory postsynaptic currents evoked by glutamate receptors (e.g. NMDA) in the spinal cord (Endres-Becker et al., 2007; Spahn et al., in press; Zöllner and Stein, 2007). The result is decreased transmission of

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μ- and δ-opioid receptors. Dynorphins can elicit both pro- and antinociceptive effects via NMDA receptors and κ-opioid receptors, respectively. A fourth group of tetrapeptides (endomorphins) with yet unknown precursors do not contain the pan-opioid motif but bind to μ-opioid receptors with high selectivity. Opioid peptides and receptors are expressed throughout the central and peripheral nervous system, in neuroendocrine tissues, and in immune cells (Stein and Machelska, 2011; Zöllner and Stein, 2007). Extracellular opioid peptides are susceptible to rapid enzymatic inactivation by aminopeptidase N and neutral endopeptidase (“enkephalinases”). Both are expressed in the central nervous system, peripheral nerves and leukocytes. Preventing the extracellular degradation of endogenous opioid peptides by enkephalinase inhibitors, both in central and peripheral compartments, has been shown to produce potent analgesic effects in many animal models and in some small human trials (Roques et al., 2012; Schreiter et al., 2012). 2.2. Opioid drugs

Fig. 3. Opioid receptor signaling and recycling, adapted from (Zöllner and Stein, 2007). Upper panel: Opioid receptor ligands induce a conformational change at the receptor which allows coupling of G proteins to the receptor. The heterotrimeric G-protein dissociates into active Gα and Gβγ subunits (a) which can inhibit adenylyl cyclase and reduce cAMP (b), decrease the conductance of voltage-gated Caþþ channels or open rectifying K þ channels (c). In addition, the phospholipase C/phosphokinase C pathways can be activated (d) to modulate Caþþ channel activity in the plasma membrane (e). Lower panel: Opioid receptor desensitization and trafficking is activated by G protein-coupled receptor kinases (GRK). After arrestin binding, the receptor is in a desensitized state at the plasma membrane (a). Arrestin-bound receptors can then be internalized via a clathrin-dependent pathway, and either be recycled to the cell surface (b) or degraded in lysosomes (c).

nociceptive stimuli at all levels of the neuraxis and profoundly reduced perception of pain. Endogenous opioid receptor ligands are derived from the precursors proopiomelanocortin (encoding β-endorphin), proenkephalin (encoding Met-enkephalin and Leu-enkephalin) and prodynorphin (encoding dynorphins). These peptides contain the common Tyr-Gly-Gly-Phe-Met/Leu sequence at their amino terminals, known as the opioid motif. β-Endorphin and the enkephalins are potent antinociceptive agents acting at

The commonly available opioid drugs (morphine, codeine, methadone, fentanyl and its derivatives) are μ-opioid agonists. Naloxone is a non-selective antagonist at all three opioid receptors. Partial agonists must occupy a greater fraction of the available pool of functional receptors than full agonists to induce a response of equivalent magnitude. Mixed agonist/antagonists (buprenorphine, butorphanol, nalbuphine, pentazocine) may act as agonists at low doses and as antagonists (at the same or a different receptor type) at higher doses. Such compounds typically exhibit ceiling effects for analgesia and they may elicit an acute withdrawal syndrome when administered together with a pure agonist. All three opioid receptors (μ, δ, κ) mediate analgesia but differing side effects. μ-Opioid receptors mediate respiratory depression, sedation, reward/euphoria, nausea, urinary retention, biliary spasm and constipation (McNicol, 2008). κ-Opioid receptors mediate dysphoric, aversive, sedative and diuretic effects. δ-Opioid receptors mediate reward/euphoria, respiratory depression and constipation (Zöllner and Stein, 2007). Immunosuppressive effects of opioids were frequently proposed in experimental but have not been verified in clinical studies (Brack et al., 2011). Tolerance and physical dependence may occur with prolonged administration of pure agonists, and abrupt discontinuation or antagonist administration can result in a withdrawal syndrome (Spahn et al., in press). Novel opioid receptor ligands acting exclusively in the periphery without central side-effects are being developed. A common approach is the use of hydrophilic compounds with minimal capability to cross the blood–brain-barrier. Among the first compounds were the μ-opioid receptor agonist loperamide (hitherto known as an antidiarrheal drug) and the κ-opioid receptor agonist asimadoline. Peripheral restriction was also achieved with glucuronidation, arylacetamide (ADL 10-0101), morphinan-based (TRK820, HS-731), triazaspiro (DiPOA) and peptidic compounds (DALDA, FE200665, CR845) (Stein and Machelska, 2011). While earlier attempts to demonstrate peripheral opioid analgesia in healthy tissue failed (Stein, 1993), potent antinociception was produced in models of nerve damage, inflammatory, visceral, cancer and bone pain (Stein and Machelska, 2011). In clinical studies peripherally restricted opioids (morphine-6-glucuronide) have been shown to reduce visceral and postoperative pain with limited central side-effects and similar efficacy as conventional opioids (Dahan et al., 2008). Current research pursues the development of systemically applicable opioids and enkephalinase inhibitors that do not permeate blood–brain or placental barriers, aiming at the selective activation of peripheral opioid receptors (Roques et al., 2012; Schreiter et al., 2012; Stein and Küchler, 2012;

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Stein and Machelska, 2011; Vadivelu et al., 2011). In addition, gene-therapeutic approaches enhancing the expression of peripheral opioid receptors and peptides are being investigated (Machelska et al., 2009; Raja, 2012). The selective activation of peripheral opioid receptors promises advantages such as antiinflammatory actions, and the absence of side effects typical for conventional opioids (respiratory depression, cognitive impairment, addiction) or nonsteroidal analgesics (gastrointestinal ulcers, bleeding, stroke, myocardial infarction). 2.3. Tolerance Tolerance describes the phenomenon that the magnitude of a given drug effect decreases with repeated administration of the same dose, or that increasing doses are needed to produce the same effect. Tolerance is not synonymous with dependence. All opioid effects (e.g. analgesia, nausea, respiratory depression, sedation, constipation) can be subject to tolerance development, albeit to different degrees. For example, tolerance to respiratory depression, sedation and nausea often develops faster than to constipation or miosis (Collett, 1998; McNicol, 2008; Rozen and Grass, 2005). Incomplete cross-tolerance between opioids or genetic differences may explain clinical observations that switching drugs (“opioid rotation”) is occasionally useful in patients with inadequate pain relief or intolerable side effects (Ross et al., 2006). Opioid-induced adaptations occur at multiple levels in the nervous and other organ systems, beginning with direct modulation of opioid receptor signaling and extending to complex neuronal networks including learned behavior. Proposed mechanisms involved in pharmacodynamic tolerance include opioid receptorG-protein uncoupling, decreased receptor internalization/recycling and increased sensitivity of the NMDA receptor (Von Zastrow, 2004; Zöllner et al., 2008; Zöllner and Stein, 2007) (Fig. 3b). In addition, pharmacokinetic (e.g. altered distribution or metabolism of the opioid) and learned tolerance (e.g. compensatory skills developed during mild intoxication) as well as increased nociceptive stimulation by tumor growth, inflammation or neuroma formation are possible reasons for increased dose requirements (Collett, 1998; Collin et al., 1993). There is a lack of carefully controlled studies that unequivocally demonstrate pharmacodynamic tolerance to opioid analgesia (i.e. reduction of clinical pain) in patients (Carroll et al., 2004). Tolerance development may be reduced due to enhanced recycling of peripheral opioid receptors in inflammatory pain (Stein et al., 1996; Zöllner et al., 2008). 2.4. Hyperalgesia There is an ongoing debate whether opioids paradoxically induce hyperalgesia. However, upon closer scrutiny of the available data it appears that most studies have in fact shown withdrawal-induced hyperalgesia, a well-known phenomenon following the abrupt cessation of opioids (Fishbain et al., 2009; Spahn et al., in press). At ultra-high doses, occasionally encountered in extreme cancer pain, singular cases of allodynia have been observed and attributed to neuroexcitatory effects of opioid metabolites (Smith, 2000). There is no conclusive evidence that hyperalgesia occurs during the perioperative or chronic administration of regular opioid doses in patients (Fishbain et al., 2009). 2.5. Central and peripheral sites of action Opioids are effective in the periphery (e.g. topical or intraarticular administration, particularly in inflamed tissue), at the neuraxis (intrathecal, epidural or intracerebroventricular administration), and systemically (intravenous, oral, subcutaneous, sublingual or transdermal administration) (Schumacher et al., 2009; Zöllner and

Stein, 2007). The clinical choice of a particular compound or its formulation is based on pharmacokinetic considerations (route of administration, desired onset or duration, lipophilicity) and on side effects associated with the respective route of drug delivery (Schumacher et al., 2009). Systemically and spinally administered opioids can produce similar side effects, depending on dosage and rostral/systemic redistribution. For intrathecal application lipophilic drugs are preferred because they are trapped in the spinal cord and less likely to migrate to the brain within the cerebrospinal fluid. The peripheral application of opioids (and other analgesics) is an area of considerable interest because many chronic pain syndromes depend to some degree on the peripheral activation of primary afferent neurons. Topically applied or locally injected opioids produce analgesia by activating opioid receptors on primary afferent neurons. This leads to inhibition of Caþþ, Na þ and TRPV1 currents, which are activated by inflammatory agents (Endres-Becker et al., 2007; Spahn et al., in press; Stein and Machelska, 2011). Subsequently the excitability of nociceptors, the propagation of action potentials and the release of proinflammatory neuropeptides (substance P) from sensory nerve endings are inhibited (Moshourab and Stein, 2012). All of these mechanisms result in analgesia and/or antiinflammatory effects (Stein and Küchler, 2012; Stein and Machelska, 2011; Stein et al., 2003). Mechanisms accounting for the particular efficacy of peripheral opioids in pain associated with inflammation include upregulation (Pühler et al., 2004) and accelerated centrifugal transport of opioid receptors in sensory neurons (Hassan et al., 1993), enhanced G-protein coupling of peripheral opioid receptors (Zöllner et al., 2003), and disruption of the perineural barrier facilitating access of opioid receptor agonists to their receptors (Antonijevic et al., 1995; Rittner et al., 2012, 2009b). Consistently, the perineural application of opioids along uninjured nerves does not reliably produce analgesic effects (Picard et al., 1997), whereas peripherally active opioids can produce significant antinociceptive effects in models of nerve injury inducing neuropathic pain (Labuz et al., 2009; Obara et al., 2007, 2009). Interestingly, endogenous opioid peptides from immune cells within inflamed tissue appear to produce additive/synergistic interactions rather than tolerance at peripheral opioid receptors (Likar et al., 2004; Stein et al., 1996; Zöllner et al., 2008). Peripheral opioid administration is regularly used and well documented in the case of perioperative intraarticular morphine (Kalso et al., 2002; Stein, 2012; Stein et al., 1991; Valverde and Gunkel, 2005). Intraarticular morphine also produces analgesia in chronic rheumatoid and osteoarthritis where its effect was shown to be similarly potent to standard intraarticular steroids and long lasting, possibly due to morphine's antiinflammatory activity (Stein et al., 1999; Stein and Küchler, 2012). In numerous small clinical studies, locally applied opioids (e.g. dermal formulations, gels) have shown analgesic efficacy in the treatment of skin ulcers, cystitis, cancer-related oral mucositis, corneal abrasion, neuropathic pain and bone injury. No significant adverse effects have been reported so far (reviewed in (Farley, 2011; Sawynok, 2003; Stein and Machelska, 2011). 2.6. Opioid receptor antagonists Opioid-related constipation is mediated by intestinal and (partially) through central μ-opioid receptors (Holzer, 2009; Zöllner and Stein, 2007). It is the most commonly occurring side effect of opioid medication in surgical and cancer patients and frequently does not exhibit tolerance. Therapeutic recommendations include laxatives and opioid receptor antagonists (Stein and Kopf, 2013). To avoid central effects reducing analgesia or producing withdrawal, oral naloxone and the peripherally restricted antagonists methylnaltrexone and alvimopan were developed. Although some studies demonstrated reversal of constipation, their use in clinical practice is limited by relatively low

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response rates, adverse effects and high costs (Diego et al., 2011; Holzer, 2009).

3. Clinical problems associated with opioid use

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pruritus) may be less dominant. Physicians and nurses may overestimate tolerance, addiction and sedation but underestimate dependence. A paramount concern is the maintenance of adequate perioperative opioid dosing to prevent withdrawal (Carroll et al., 2004; Richebe and Beaulieu, 2009; Stein and Kopf, 2013).

3.1. Dependence and addiction Physical dependence is defined as a state of adaptation that is manifested by a drug class-specific withdrawal syndrome that can be elicited by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist (Savage et al., 2003). All opioids produce clinically relevant physical dependence, even when administered only for a relatively short period of time (Compton et al., 2004). Thus, all patients with continuous opioid intake should be considered at risk for withdrawal syndrome if opioid medication is decreased (e.g. inadvertently during or after surgery). Opioid withdrawal symptoms, especially tachycardia and hypertension may be detrimental for the high risk cardiac patient. Addiction is a behavioral syndrome characterized by evidence of psychological dependence (craving), uncontrolled/compulsive drug use despite harmful side effects, and other drug-related aberrant behaviors (e.g. altering prescriptions, manipulating health care providers, drug hoarding or sales, unsanctioned dose escalation) (Hojsted and Sjogren, 2007; Savage et al., 2003). Reviews indicate that the prevalence of opioid addiction is as high as 50% in patients with chronic non-malignant pain and up to 8% in patients with cancer pain (Hojsted and Sjogren, 2007; Martell et al., 2007). Many issues regarding opioid-consuming chronic pain patients also apply to patients who abuse or are addicted to opioids. The daily dose of opioids in abusing or addicted patients is typically larger, such patients often have coexisting psychiatric diseases (depression, anxiety, psychosis), and the known history of abuse may lead to a tempered use of opioids by healthcare providers (Carroll et al., 2004).

3.3. Long-term opioid use in chronic non-malignant pain In contrast to acute and cancer-related pain, the long-term use of opioids in chronic non-cancer (e.g. neuropathic, musculoskeletal) pain is highly controversial. So far, RCTs have only been conducted for a maximum period of three months. In metaanalyses the reduction of pain scores was clinically insignificant and epidemiological data suggest that quality of life or functional capacity are not improved (Eriksen et al., 2006; Stein et al., 2010). Adverse side effects (nausea, sedation, constipation, dizziness etc.) and lack of analgesic efficacy led to the drop-out of high numbers of subjects, both in RCTs and in uncontrolled observational studies beyond three months (Gustavsson et al., 2012; Noble et al., 2010; Stein et al., 2010). Psycho-social outcome parameters were rarely investigated and showed only modest improvement. Thus, consistent with the multifactorial nature of chronic pain, it is unlikely that opioids alone can produce an analgesic response if, for example, there is a major affective component or if learned pain behavior is the main problem (Fordyce, 1991; Stein, 1997). The target of intervention is not only the source of nociception (if at all identifiable) but suffering, dysfunction, psychosocial factors and dependence on the health care system. In addition, addiction has been reported in high numbers of such patients (see above), and overdoses, death rates and abuse of prescription opioids have become a public health problem (Hojsted and Sjogren, 2007; Martell et al., 2007; Paulozzi et al., 2012; Von Korff et al., 2011). Thus, the use of opioids as a sole treatment modality in chronic non-malignant pain is not recommended.

3.2. Acute pain management in the chronic pain patient The management of acute pain (e.g. associated with surgery) is complicated in the chronic pain patient. Perioperative management has to address the risk of opioid withdrawal, the altered pain sensitivity, and the psychological alterations typical in this patient population (Stein and Kopf, 2013). Chronic pain patients are often treated with opioids, COX inhibitors, antidepressants and/or anticonvulsants. Tolerance, drug interactions and side effects occur, and inappropriate or excessive medication is commonly observed (Bigal et al., 2004; Paulozzi et al., 2012; Von Korff et al., 2011). Chronic opioid medication has been promoted in the literature and, together with aggressive marketing, this has gradually led to decreasing reservations towards these drugs among practitioners. As a result, opioids are used more frequently in both cancer and non-cancer pain patients and the majority of the latter are now prescribed long-term opioid medication (Breivik et al., 2006; Paulozzi et al., 2012; Von Korff et al., 2011). Such treatment can result in increased and prolonged requirement for analgesics after surgery compared to opioid-naïve patients (Carroll et al., 2004; Hadi et al., 2006; Richebe and Beaulieu, 2009; Rozen and Grass, 2005). Chronic pain patients with prior opioid consumption may also exhibit higher postoperative pain scores (Richebe and Beaulieu, 2009). The increased postoperative analgesic demands may be due to lower pain thresholds or to a need for higher drug concentrations. In addition, opioid requirements can be influenced by gender, genetic predisposition, age, type of surgery and preoperative pain levels (Ross et al., 2006; Slappendel et al., 1999). On the other hand, opioid-related side effects (e.g. nausea and

4. Conclusions Opioids are the oldest and most potent drugs for the treatment of severe acute and cancer pain. However, the long-term use of opioids in chronic non-malignant pain has not proven effective in improving pain intensity or quality of life. Instead, addiction, overdoses, death rates and abuse of prescription opioids have reached epidemic proportions and have become a public health problem. Thus, the use of conventional opioids as a sole treatment modality in chronic non-malignant pain is not recommended. Beyond the usual systemic and central routes of opioid administration, the potential of peripheral actions is increasingly recognized and used by clinicians. Peripheral opioid receptor activation may produce potent analgesia, less tolerance and fewer side effects such as addiction, sedation, nausea or respiratory depression. In line with current research efforts aimed at preferential targeting of peripheral sensory neurons, this could be a promising approach in the development of novel therapeutics for pain.

Acknowledgments This article was adapted from (Stein and Kopf, 2013). Supported by Bundesministerium für Bildung und Forschung (ImmunoPain 01 EC 1004 C; Medical Systems Biology—0101-31P5783; VIP0272, AZ 16V0364) and Helmholtz-Gemeinschaft.

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