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THE HEALING CRISIS IN ADDICTION AND HEALTH RECOVERY

Jun 03, 2014 - 6 comments

This is what i believe to be vital information for many of us that don't understand what can and may happen on the road to recovery or detoxing from and health or addiction issue's. Right down to dietary change's, exercising more,  dropping caffeine, smoking lot's of things. Love Tswana xxx

HEALING CRISIS

The Road to Better Health

by Walter Last

I routinely recommended to my patients right on their first visit to adopt a high-quality, low-allergy diet. When they came back two or three weeks later, they often said that they feel much better now but a week ago they had a cold. When I asked about the symptoms they turn out to be mainly a profuse mucus discharge, sometimes also diarrhoea, but rarely are there signs of a real infection. In fact, these patients just experienced their first healing crisis on their long path to better health.

This concept of a healing crisis clearly shows the opposite perceptions that drug medicine and holistic medicine have of health and the healing process. In drug medicine it is assumed that a patient who is free of disease symptoms is more or less healthy and the aim of drugs is to achieve this condition by removing any disagreeable symptoms. Frequently alternative or complementary medicine is used in the same way, instead of more or less toxic drugs just more benign remedies are being used. This is what most patients want and according to their beliefs they either use drugs or natural remedies for this purpose.

However, holistic or natural medicine, following in the footsteps of the old nature cure movement, aims much higher. Here, health is regarded not just as a temporary absence of disease symptoms, but as a state of profound physical, emotional and mental wellbeing so that we simply cannot develop or catch a disease.

Animals living in an unspoiled natural habitat in the wild commonly display this kind of health. If we want to come close to such outstanding health, we have to work for it by consciously minimising the multitude of negative influences on our health and maximise positive factors instead.

However, experience shows that we do not follow a straight line of either health improvement or health deterioration. Similar to periods of illness interspersing times of relative wellbeing on the common road to chronic degenerative diseases and death, so we have also ups and downs on the road to superior health. The main difference is that the road to deteriorating health on average is sloping downhill while the other road on average goes up in health. Travelling downhill is easy, we do not need to do anything about it, but improving our health requires consistent effort.

Contrary to the often-lengthy periods of ill health on the downhill road, the dips on the uphill road are usually short and sharp. They are called 'healing crisis' although I prefer the less dramatic name 'healing reaction', also 'cleansing reaction' or simply 'reaction'. After each reaction we advance to a higher level of health than before the reaction.

Holistic therapists realise that the road to better health follows a definite pattern. The old school of nature cure called it

HERING'S LAW OF CURE:

"All cure starts from within out, from the head down and in reverse order as the symptoms have appeared."

Dr John Whitman Ray has developed a method specifically designed to help us travel the long road to superior health. He called it Body Electronics, using nutrition as well as press point therapy to facilitate emotional release and expansion of consciousness. Out of this work Dr Ray found it necessary to modify Hering's Law to the following

LAW OF HEALING CRISIS:

"A healing crisis will occur only when an individual is ready both physiologically and psychologically. The basic foundation for all healing is nutritional preparedness. A healing crisis will begin from within out, in reverse order chronologically as to how the symptoms have appeared, tempered by the intensity of the trauma. The individual will have the opportunity to re-experience each trauma, both physiological and psychological, beginning with the trauma of least severity. It must be recognised that traumas involving emotions, which include all traumas, will be released in order, beginning with unconsciousness, then apathy, grief, fear, anger, pain and eventually enthusiasm (love), in conjunction with the appropriate word patterns for each emotion and thought pattern (sensory memory) which are accessible at each level. Unconditional love and unconditional forgiveness are the keys to apply and transmute any resistance at any level, once these resistances are brought to view through the application of the laws of love, light and perfection.

With this definition Dr. Ray emphasises the importance of the emotional side of our health problems. Each disease, accident or surgical intervention contains a strong emotional component which needs to be re-experienced during a reaction, otherwise the healing will remain incomplete and the problem will present itself again at a later time for healing at a deeper level.

This also means that the body selects the kind of healing crisis that is most appropriate at the time, taking into consideration its needs and abilities to have a certain area healed or improved. We can consciously influence this choice by working on a particular problem. I also noticed that the body self tries to select a timing, which does not disable us during important events coming up. I have no doubt that we are guided on our healing path by our inner intelligence, which has our best interest at heart.

In the beginning our healing reactions will be mainly on the physical or biological level, but more and more we will experience the release of emotional blocks and changes in consciousness, preparing us for greater activity on the spiritual level.

PATTERNS OF HEALING

In every real healing, the sequence of our health deterioration will automatically be retraced. This means that old, long-forgotten disease symptoms may suddenly flare up again in the form of a healing crisis. The reason for this is based on the very nature of disease.

At first, when the body is still vital, it will react forcefully against invaders; the resulting battle causes fever and inflammation. If the body is not strong enough to win completely, the acute battle symptoms will eventually subside, with the remaining invaders leading a somewhat subdued existence in a weakened gland or organ. Repeated attacks will result in the degeneration of this body part, causing chronic disease.

At some stage on the road towards health, the body will feel strong enough to start the fight again for healing the diseased organ, and inflammation will result. Such healing reactions are usually short lived, but can be rather violent. If one supports the body during this period with rest, cleansing diets and so forth, then the organ will eventually acquire a much better health than before the flare-up. If, however, drugs are used to suppress the healing symptoms, then the inflamed organ will return to its subacute, chronic condition and wait for another opportunity to heal itself

The healing pattern of other health problems that are not related to immunological processes and infections follows a similar line to that outlined above. Healing takes place on many different levels: at the biochemical level within the cells, in the blood circulation, the nervous system and especially in the flow of bio-energies. Healing activity will be increased on all of these levels

At the bio-energetic level, the increased energy flow may cause congestion at various places, in the weak body part itself as well as in related acupuncture points and zone reflex areas. Excess energy in such places may be noticed as pain, heat or tension: the common symptoms of inflammation. In time, the body itself will clear the obstruction in the energy flow.

One may support this process with specific healing methods or just by healthy living in general. However, trying to suppress any inflammation may leave the body part permanently weak Inflammation in itself is a healing energy release and it may be best overcome by removing the blockage in the energy flow.

SKIN REACTIONS

Another common form of healing reaction is the development of a rash or other skin problem, especially over a weak body part, for instance at a hip or shoulder. This skin reaction signifies that the energy that had been bound internally in this area in the form of muscle armouring, stiffness and accumulated metabolic wastes, is now surfacing and dissipating. Thus the affected joint or limb will become much freer and stronger. However, if the skin reaction is interfered with and made to go prematurely, then the suppressed energy and metabolic waste will remain in that body part, keeping it in a state of pain or weakness.

Thus there usually is no need to interfere directly with skin diseases or other healing symptoms. On the contrary, that may only drive the problem 'underground' to affect internal organs and body structures. Natural healers have noticed that by artificially producing a rash over an arthritic joint, the joint greatly improved, but when a rash over a joint was artificially suppressed, then arthritic symptoms may appear in that joint.

You may actually learn much about yourself, your body, your health problems and your emotional reactions by patiently observing the healing process instead of rushing in to do something about it. What you should do, however, is live healthily in general, cleansing the body, helping the suppressed energy to come out and dissipate and to be optimistic about it all.

Frequently, boils and increased mucus discharge (colds) may appear during the initial stages of the healing process, sometimes starting already one or two weeks after improving the diet and beginning to take supplements. This indicates that the organs of elimination are congested. During Such times take little food, but generous amounts of herb teas, fresh vegetable juices and water. Preferably go on a cleansing diet.

You may notice an advance warning of an approaching healing crisis in the iris, when a formerly grey or brown reflex area becomes whitish. At the same time, the reflex points underneath the feet and on the hands, as well as pressure points related to the activated organ, become more tender and should be pressed. Such healing crises may appear from time to time separated by weeks, months or even years bringing us ever closer to our distant goal of superior health.

LISTEN TO YOUR BODY

Some further problems may develop during health improvement. Formerly, the body responses may have been dulled - it did not react to harmful foods or drugs - but now the reaction is often immediate and forceful.

Foods that you may have eaten habitually before going on a cleansing diet may suddenly cause a gastro-intestinal upset, making you feel sick and miserable for days. However, such reactions do not need to happen if you take proper precautions: find out to which foods you are allergic and try to avoid these as well as foods that may be a problem for you. If you eat out and do not know what to expect, take plenty of digestive enzymes and lecithin during the meal, and try to eat foods in correct combination; if allergy symptoms appear, use alkalisers together with calcium ascorbate.

Basically, one may say that your body now trusts that you will not hurt it any more in the old ways. But if you do, your body is very offended and lets you (your mind) know about it in no uncertain terms. This is the most effective language that your body has. However, if you learn to listen, your body will first try to tell you about its requirements in a more subtle way - an intestinal rumbling, an itch, a slight muscle weakness or a passing pain. There are numerous ways a body expresses its needs and each one has its own language of symptoms.

Furthermore, if you are honest and persistent in your desire to become a friend of your body, it will eventually let you know its needs by intuition, by its likes and dislikes, you will rediscover your lost body instincts. This is what we really should aim for: to become independent of outside expert advice and just do what our body tells us is right for us to do, not only in the field of nutrition, but in everyday living and with important decisions as well.

While one can usually gain relatively quick relief from distressing disease symptoms, rebuilding a strong and healthy body is a slow process and takes a long time. It requires a great deal of experimenting in order to find our individual conditions for healing, and it also needs solid determination to carry through with a program for many years.

Generally, recently acquired chronic weaknesses are the first to flare up and become healed, while our oldest and most persistent health problems are the last to yield. Thus there appears to be an orderly sequence in our health improvement. Healing proceeds in a wave pattern with an upward slope. On the peak of a wave we feel much improved, while in a trough we experience cleansing activity or a healing reaction and feel down. The overall movement, however, is towards greater wellbeing.

Just looking at the symptoms of a reaction, you will not be able to distinguish a healing crisis from a disease crisis -a flare-up on the downhill road to degenerative disease. In fact, the symptoms are the same because the underlying process is the same.

The body always tries to heal itself and an acute inflammation is an important tool for this purpose. An inflammation makes the walls of the blood vessels porous to allow an increased flow of lymph fluid to move in immune cells and remove accumulated toxins. At this stage it is just an acute inflammation and we can choose to turn it into a healing crisis by supporting the body mentally and nutritionally or we can choose to suppress the acute condition and return to a chronic degenerative condition.

Therefore, anything that suppresses an acute inflammation prevents healing of the affected area. This includes not only anti-inflammatory drugs and remedies, but also strong alkalisers that reduce the release of histamine. The pain and heat in the inflamed area is the price we have to pay for it being healed.

However, anti-inflammatory agents and alkalisers have their place to ease the discomfort of a chronic inflammation until the body has been nutritionally and mentally prepared for a healing reaction. Furthermore, the symptoms during a reaction may either be too severe or come at an inopportune time. Then you can lessen or temporarily stop them by adding cooked food to a raw food cleansing diet or by alkalising the body and using anti-inflammatory remedies.

Usually we can select a suitable time for a healing crisis by starting a strict cleanse on raw food only, especially fresh vegetable juices or fruit, possibly also vegetable salads. A fruit cleanse is more suitable for insensitive individuals and vegetables are much better with an over-acid and sensitive body.

One of the main factors reducing the severity of any symptoms is a clean bowel, regardless whether the reaction was triggered deliberately or involuntarily. The easiest way to do this is by taking a tablespoon of Epsom salts (more or less according to bowel reaction) in water at bedtime or on rising. If no solid food is used then take a teaspoon of psyllium hulls several times daily in a glass of unchloriated water. Too little water can cause constipation.

Another way to ease or shorten a reaction is press-point therapy: strongly press into tender points on the feet and body related to problem areas until the points lose their tenderness. This may take hours or days with some key points. You can further support your body with light, enjoyable outdoors activity. Also prayer and meditation or guided imagery are recommended.

As you can see, there is no simple path to completely avoid health-related suffering. We can only choose in which way we want to suffer. We can either deliberately and cheerfully endure the unpleasantness of repeated healing crises with the promise of better health to follow, or we can expect to suffer involuntarily and in an uncontrolled way from chronic-degenerative diseases as we get older. The choice is ours.


Hi everyone xxxxxx

Apr 02, 2014 - 0 comments

Long time no see :-D I am still on my journey and the road is long BUT i'm still walking it. Yes!!! i had times of despair and the dreaded PAWS got too much, is too much to post regularly for a while. And many others facets that go hand in hand with healing.

And also all good pupils learn in order to help not just themselves but others too no matter what during your recovery and no matter what you know you got to be like the wise Ancients.

Go sit at the top of the Mountain by yourself and quietly and be your own Teacher as well. And contemplate that your plans can't be static as many things will rise up along your journey such is the way of life.

Making changes to adapt doesn't mean your doing it wrong just you need to adapt. In the Universal law of balance there is no right or wrong way but acceptance that there has to be changes good or bad in personal reconstruction.

BUT this also doesn't mean that bad is bad it's just that it's its time and a good thing depending on your perception. Why!!! the very fabric of the universe its self is infinitely changing and we are ALL part of that fabric of change:

And resistance to change is the worse thing you can have for that means non acceptance of what is. And therefore your holding back change by seeing change as a problem its not  its PROGRESSION letting you know you need to turn left or right on your path to get ahead.   Love, Peace, Harmony Tswana xxxxx


Opioid-induced hyperalgesia

Mar 24, 2014 - 2 comments

THE ONLY CURE UNFORTUNATELY IS TO NOT TAKE ''ANY PAINKILLERS'' OPIATE OR OTHERWISE!!!! AND IT WILL TAKE TIME FOR YOU TO RECOVER!!! BUT IT CAN BE DOEN!!! PLEASE DON'T GO TO A DOCTOR THEY WILL GIVE YOU METHADONE OR KETAMINE OR GARBBBAPPETIN, PREGABLIN (LYRICA) THEY MAY WORK FOR A SHORT TIME BUT.....THE END RESULT IS THE SAME!!! AND IT WILL JUST PROLONG YOUR SUFFERING!!! I SWEAR MAY GOD TAKE ME NOW!!! I CRY FOR THE WORLD FOR THIS GOD AWFUL SIN THAT HAS BEEN PUSHED ON US ALL!!! I HAVE TRIED EVERTYTHING!!! AND EVERY TIME THE AGONY SOON BREAKS THROUGH!!! YOU WILL HAVE BAD DAY'S AND SUPER BAD DAY'S BUT THE ONLY WAY IS TO LET GOD'S WOPRK DO IT'S WORTK!!! I NOW UNDWERSTAND WHY CHRIST SREAMED ''ELOI!! ELOI!!! ''MY GOD! MY GOD! WHY HAST THOU FROSAKEN ME??? WE JUST GOT TO TOUGH OT OUT!!! SOME DAY'S WILL FEEL LIKE A MIRACLE AND THEN??? HELL AGAIN!! BUT YOU GOT TO LET IT TAKE ITS PATH AND ITS VERY HARD!!! EAT AS BEST FOOD AS YOU CAN AND STAY HYDRATED AND PLENTY OF NIACIN AND VIT C. IF I CAN FIND N E THING ELSE TO HELP I WILL POST IT XXXX

Opioid-induced hyperalgesia - Wikipedia, the free encyclopedia  FOR GOD'S SAKE PLEASE READ THIS!!!!!!!

Mar 24, 2014 - 2 comments

Mechanisms of Opioid-Induced Tolerance and Hyperalgesia

Anna DuPen, MN, ARNP;* Danny Shen, PhD;‡ Mary Ersek, PhD, RN†Pain Manag Nurs. 2007;8(3):113-121. ©2007 Elsevier Science, Inc.
Posted 09/05/2007

Abstract and Introduction

Abstract

Opioid tolerance and opioid-induced hyperalgesia are conditions that negatively affect pain management. Tolerance is defined as a state of adaptation in which exposure to a drug induces changes that result in a decrease of the drug's effects over time. Opioid-induced hyperalgesia occurs when prolonged administration of opioids results in a paradoxic increase in atypical pain that appears to be unrelated to the original nociceptive stimulus. Complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying opioid tolerance. Pain facilitatory mechanisms in the central nervous system are known to contribute to opioid-induced hyperalgesia. Recent research indicates that there may be overlap in the two conditions. This article reviews known and hypothesized pathophysiologic mechanisms surrounding these phenomena and the clinical implications for pain management nurses.

Introduction

Opioid analgesics continue to be the mainstay of pharmacologic treatment of moderate to severe pain. Many patients, particularly those with advanced cancer, require chronic high-dose opioid therapy. Achieving clinical efficacy and tolerability of such treatment regimens is sometimes hindered by two opioid-related phenomena. The first is tolerance, which is manifested clinically by the need for increasing opioid dosages over time to maintain the same level of pain relief; this increased need is not explained by disease progression. A second problem that arises is the more recently recognized phenomenon of opioid-induced hyperalgesia (Sjogren et al., 1998). In this situation, prolonged administration of opioids results in a paradoxic increase in atypical pain that appears to be unrelated to the original nociceptive stimulus.

Opioid-induced tolerance and hyperalgesia have been documented in both animal and human studies. They can develop after administration of several types of opioids delivered via various routes, doses (i.e., ultra-low through high dosages), and administration schedules (i.e., intermittent vs. continuous) (Angst & Clark 2006, Mao 2006, Ossipov et al 2005). Cellular changes associated with these phenomena have been identified at many anatomic sites, including afferent neurons, the spinal cord, brain, and the descending modulatory pathway (Gardell et al 2006, King et al 2005, Mao et al 2002, Ossipov et al 2005, Terman et al 2004).

Significant clinical challenges arise from opioid-induced tolerance and hyperalgesia. More effective pain treatment can be achieved when these conditions are recognized and managed. Although the mechanisms underlying opioid-induced tolerance and hyperalgesia are not completely understood, research has begun to reveal some of the complex factors that are associated with these phenomena. The purpose of the present article is to describe both the established and the hypothesized mechanisms underlying opioid-induced tolerance and hyperalgesia. The clinical implications of these mechanisms and their possible prevention and treatment also are discussed.

Opioid Receptor Physiology

A discussion of opioid tolerance is best prefaced with a review of opioid receptor physiology. Researchers have identified three types of opioid receptors: mu, delta, and kappa receptors. These receptors are distributed in various locations within the spinal cord and brain structures. Figure 1 shows the distribution of opioid receptors in the brain of a guinea pig. Mu opioid receptors are highly concentrated in the outer laminae of the dorsal horn of the spinal cord, whereas delta opioid receptors are diffusely distributed throughout the dorsal horn (Quirion 1984, Quirion et al 1983). Kappa opioid receptors are concentrated in the outer laminae of the dorsal horn of the lumbosacral cord and are closely associated with neural input from the visceral structures (Quirion 1984, Quirion et al 1983). Two areas of the brainstem—the rostral ventromedial medulla (RVM) and the periaqueductal gray (PAG)—express high levels of mu opioid receptors; delta and kappa receptors are also expressed, albeit at much lower levels (Mansour et al 1987, Mansour et al 1995). Studies have demonstrated mu and some delta opioid receptors on neurons that arise from the PAG or RVM and descend to the spinal cord where they inhibit pain transmission (Van Bockstaele et al., 1996).

    Figure 1. Image of guinea pig brain; red areas represent highest density, yellow areas represent moderate density, and blue, purple, and white represent low density of opioid receptors. Reprinted with permission from Solomon H. Snyder, MD, Department of Neuroscience, Johns Hopkins Medical School.

Clinically available and experimental opioids have differing potency and efficacy at the various opioid receptors. The overall action of a particular opioid is the sum effect of activation of all the relevant receptors. Most of the opioids that are currently used in clinical practice are predominantly mu agonists (although some also bind at delta or kappa receptors or both). There are at least seven "subtypes" of the mu receptor (Pasternak, 2001), and each opioid may have different affinities for the various mu receptor subtypes. Tolerance may develop separately at each mu receptor subtype in response to a particular opioid. When a patient is switched from one opioid to another, the "new" opioid may have a different selectivity for the individual mu receptor subtypes, which explains "incomplete" cross-tolerance and offers a way to overcome tolerance.

This difference in how opioids interact with the mu receptor subtypes and/or their ability to activate the other opioid receptor types could explain or predict clinical differences in the pharmacologic effect of one opioid compared with another. Moulin et al. (1988) studied tolerance in morphine versus levorphanol, an opioid that is active at all three opioid receptors. Pretreatment with levorphanol in rats caused tolerance to morphine and levorphanol, but pretreatment with morphine caused tolerance only to morphine and not to levorphanol, indicating that receptor selectivity influences tolerance (Moulin et al., 1988). More recently, investigators have postulated that the ability of methadone to differentially activate delta opioid receptors may be a contributing factor to its incomplete cross-tolerance in patients who had become tolerant to mu opioids such as morphine (Lynch, 2005).

Some investigators have postulated that genetic variations in receptors, often referred to as genetic polymorphism, can account for interindividual differences in pain sensitivity, opioid analgesic response, and risk of psychologic dependence (Bond et al 1998, Estfan et al 2005, Thomsen et al 1999). Approximately 500 genes have been identified that influence pain in animal and human studies, with about 100 variations in the human mu opioid receptor gene alone (Ross et al., 2006). At present, the functional significance of many of these pain-related and opioid receptor genetic variants has not been fully elucidated. For example, the A118G genetic variant of the mu opioid receptor, which results in a change in amino acids from asparagine to aspartate at position 40, has been studied in both pain (Hirota et al 2003, Lotsch et al 2002, Lotsch et al 2002, Ross et al 2005) and addiction (Bergen et al 1997, Bond et al 1998, Li et al 2000, Sander et al 1998, Town et al 1999), with conflicting reports on its relationship to morphine potency or its association with risk of substance abuse. A recent study explored the influence of variations in genes that encode the mu opioid receptor and its regulatory proteins on opioid response in a cancer patient population. There were no significant differences in the frequency of several variants of mu opioid receptor genes between patients responsive to morphine and those intolerant of morphine. There were, however, significant differences in frequency of two genetic variants (i.e., stat6, mu opioid gene transcriptional factor; and -arrestin2, intracellular regulatory protein) between patients who required a switch from morphine to an alternative opioid compared with those who obtained adequate analgesia with morphine (Ross et al., 2005). These differences suggest that genetic variations among individuals influence clinical responses to morphine and possibly other opioids.

Opioid Tolerance

Opioid-induced tolerance is described in the simplest pharmacologic terms as a shift to the right in the dose-response curve; in other words, a higher dose is required over time to maintain the same level of analgesia. At times, progressive disease is the reason for higher opioid requirements (Collin et al 1993, Foley 1993). Other causes of increased opioid needs are pharmacokinetic or pharmacodynamic changes. Pharmacokinetic changes occur, for example, if the drug up-regulates the activity of a metabolic process that represents a major pathway for its elimination from the body. Enzyme induction results in a gradual reduction in plasma drug concentration while the daily opioid dose remains unchanged. Pharmacodynamic tolerance occurs when a decline in drug effect cannot be attributed to pharmacokinetic factors but instead reflects drug-activated changes in the response of the neural systems. For our purposes, "opioid tolerance" refers to pharmacodynamic tolerance.

Two major theories of opioid tolerance involve changes in opioid receptors. One theory purports that receptors undergo changes that result in decreased receptor activation, or desensitization, with prolonged exposure to opioids. The other line of evidence suggests that opioid receptor down-regulation is at least partially responsible for the development of tolerance.

The desensitization mechanism involves changes in the physiology of the opioid receptors. These receptors belong to the family of G protein–coupled receptors (GPCRs). When the opioid is bound to the receptor, the associated G protein becomes "activated." Activation of G proteins eventually leads to decreasing excitability along the cell membranes of neurons in the pain pathways. This action occurs through a reduction in cyclic adenosine monophosphate (cAMP), leading to a suppression of Na+ and Ca+ channels and resulting in analgesia (Figure 2). Over time, alterations in the G protein–mediated mechanism can lead to decreased analgesia through opioid receptor desensitization (Ferguson et al 1998, Luttrell & Lefkowitz 2002, Perry & Lefkowitz 2002, Raehal & Bohn 2005, Shen & Crain 1990, Terman et al 2004, Wang et al 2005, Yoburn et al 2003). In animal models, this desensitization occurs when intracellular regulatory proteins or enzymes, such as GPCR kinases, -arrestins, and adenylyl cyclase, are activated by opioids in such a way that they "decouple" the opioid receptor from the G protein or produce a "switch" in coupling of the receptor to a "nonanalgesic" G protein, subsequently decreasing analgesic activity. Receptor desensitization has been previously associated with morphine tolerance in rats (Noble & Cox 1996, Sim et al 1996), but more recent reviews underscore how much is left to be learned about these complex intracellular mechanisms (Raehal & Bohn, 2005).

    Figure 2. Schematic of opioid receptor mechanism.

A second mechanism believed to be responsible for opioid tolerance occurs via internalization of the opioid receptor from the cell membrane. The density of opioid receptors located on the cell membrane is governed by endocytosis, whereby the cell membrane closes around the receptor, effectively creating a bubble of cell membrane around the receptor and drawing it into the body of the cell. Once inside the intracellular environment the receptor can no longer function and is effectively down-regulated. Rats lacking one of these down-regulators (-arrestin2) continue to have prolonged morphine-induced analgesia, whereas their counterparts that do have this down-regulator develop "tolerance" to the analgesic effects (Bohn et al 2002, Bohn et al 1999). Despite this evidence, some researchers have suggested that increased internalization may actually decrease tolerance by getting desensitized receptors off the membrane and causing resensitization through new or recycled receptors being substituted (Finn & Whistler, 2001).
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Various opioid agonists (e.g., morphine, methadone, fentanyl) have been shown to differ in their ability to desensitize or down-regulate opioid receptors (Arden et al 1995, Sim-Selley et al 2000, Yabaluri & Medzihradsky 1997). Some of these differences have been attributed to the "intrinsic efficacy" of the opioid agonist. Each opioid has a given level of intrinsic efficacy for the various opioid receptors. Intrinsic efficacy is a conceptual parameter that relates the number of receptors occupied to the magnitude of the receptor-mediated response. To generate a given effect, it is necessary to occupy a number of receptors out of the total population, the so called "fractional receptor occupancy" (Chavkin & Goldstein 1982, Mercadante 1999). The number of receptors that need to be occupied to create an analgesic effect is believed to be inversely proportional to the intrinsic activity; in other words, the larger the number of unoccupied receptors (receptor reserve) that exist when a drug achieves analgesia, the greater the intrinsic efficacy of the drug (Chavkin & Goldstein 1984, Duttaroy & Yoburn 1995, Ivarsson & Neil 1989, Sosnowski & Yaksh 1990).
In general, continuous treatment with opioids with lower intrinsic efficacy, such as morphine, have been known to cause a larger rightward shift in dose response (i.e., tolerance) (Saeki & Yaksh, 1993). Animal studies have shown that chronic treatment with high-efficacy opioids that have a significant receptor reserve, such as fentanyl, down-regulate fewer receptors (Sosnowski & Yaksh, 1990). However, recent studies show high-efficacy opioids actually activate more receptor-desensitizing substances (G protein–coupled receptor kinases) than low-efficacy opioids (Terman et al., 2004), leaving us again with more complexity than clarity on these opioid-related intracellular mechanisms.

Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia is a condition manifested clinically as hyperesthesia (i.e., dramatically increased sensitivity to painful stimuli) and/or allodynia (i.e., pain elicited by a normally nonpainful stimulus). It occurs in some patients (and, in laboratory studies, animals) receiving chronic opioid therapy; the abnormal pain often arises from an anatomically distinct region and is of a different quality than the original pain problem (Ossipov et al., 2005). Clinical reports dating back to the late 19th century documented that hyperalgesia was associated with opioid dependence. Later clinical observations and studies suggested that pain sensitivity differs between persons with opioid addiction and those who are not addicted (Compton 1994, Doverty et al 2001). In the 1940s, hyperalgesia also was described as part of the opioid withdrawal syndrome. In the past decade, research indicated that hyperalgesia also occurred in the context of short-term and continuous therapy in which physical dependence and withdrawal did not play a role (Angst & Clark, 2006).

Several mechanisms associated with opioid-induced hyperalgesia have been identified. Glutamate-associated activation of N-methyl-D-aspartate (NMDA) receptors causes spinal neuron sensitization; this pronociceptive mechanism has been implicated in the development of neuropathic pain and opioid-induced hyperalgesia. The ability of NMDA receptor antagonists such as MK801 to block opioid-associated hyperalgesia provides further evidence that NMDA receptors are involved in hyperalgesic states (King et al 2005, Mao 2006, Ossipov et al 2005).

Other studies have documented that hyperalgesia results from increased excitatory peptide neurotransmitters, such as cholecystokinin (CCK), which are released from neurons in the RVM and activate spinal pathways that up-regulate spinal dynorphin. Both of these substances act as pronociceptive agents (Dourish et al 1988, Gardell et al 2002, Vanderah et al 2000, Vanderah et al 2001, Xu et al 1992). These and other excitatory neurotransmitters are believed to cause "central sensitization" that result in hypersensitivity of the spinal cord to nociceptive inputs from the periphery. In other words, pain signals being transmitted into the spinal cord become amplified as a result of the action of these neurotransmitters.

Opioid-Induced Tolerance and Hyperalgesia: Two Sides of the Same Coin?

The major clinical manifestation of opioid-induced tolerance and that of hyperalgesia are the same; that is, increasing opioid doses are necessary to achieve adequate analgesia (Angst & Clark 2006, King et al 2005, Mao 2006). Moreover, there are similarities in the mechanisms that cause tolerance and hyperalgesia. For example, CCK-mediated changes in the descending modulatory pathways appear to contribute to both opioid-induced tolerance and hyperalgesia (King et al., 2005). There also is evidence that tolerance and hyperalgesia share common cellular mechanisms that are related to changes in NMDA receptors (Mao et al 1994, Mao et al 2002).

The similarities between mechanisms causing tolerance and hyperalgesia suggest that some targeted therapies can prevent or reverse both phenomena. While this strategy has been shown to be effective in preclinical and clinical studies, Mao urged caution with this approach (Mao 2002, Mao 2006). He pointed out that hyperalgesia is characterized by different clinical features than tolerance. These features include pain intensity that is higher than the severity of the original pain problem, pain that is poorly defined in terms of quality and location, and changes in pain threshold and tolerability. These distinct features indicate that at least some of the cellular mechanisms underlying tolerance and hyperalgesia differ between the two entities. Hyperalgesia represents increased sensitivity to pain, whereas tolerance may reflect decreased sensitivity to opioids. Most importantly, unlike tolerance, opioid-induced hyperalgesia would worsen after an increase in opioid dose, whereas pain related to tolerance would be relieved by an increase in opioid dose (Mao 2002, Mao 2006).

Clinical Implications

Pain management specialists are frequently called to consult on cases involving opioid tolerance or toxicities. Strategies for clinical management must be based on the current understanding of the complex mechanisms underlying these problems. Some strategies, such as the use of opioid-sparing therapies and opioid rotation, are currently used to prevent and treat tolerance and hyperalgesia, although the evidence supporting these practices is lacking. Other strategies such as the use of concomitant low-dose opioid antagonists to suppress G protein switching, inhibition of -arrestin2 to prevent down-regulation, or the use of CCK and NMDA receptor antagonists to suppress pain facilitation pathways are still in preclinical or early clinical studies. Pain management nurses should understand the scientific basis for current and emerging therapies.

One of the most commonly used strategies to prevent opioid tolerance and hyperalgesia is the use of adjuvant drug therapies such as anticonvulsants and antidepressants, as well as nondrug therapies such as heat, cold, and exercise programs. This approach is the cornerstone of the "opioid-sparing" principle, which aims to minimize opioid doses while providing optimal pain relief. Although there is no hard evidence that receptor desensitization or down-regulation occurs with more intensity at higher doses of opioids, many pain specialists accept the premise that an opioid-sparing treatment plan is the first step in proactively minimizing side effects and opioid tolerance (Ho et al 2006, Lauretti et al 1999, White 2005), despite evidence that challenges this principle (Kloke et al., 2000).

Opioid rotation is widely used as a treatment option to take advantage of "incomplete cross-tolerance" to recapture efficacy in a patient experiencing significant opioid tolerance or unusual sensitivity to opioid side effects. Several reports have documented success with this strategy (De Stoutz et al 1995, Drake et al 2004, Indelicato & Portenoy 2002, Kloke et al 2000, Thomsen et al 1999), although the research evidence is weak, given the poor design and small samples that characterize studies evaluating this clinical maneuver (McNicol et al 2003, Quigley 2004).

Combining opioids with low-dose opioid antagonists to prevent hyperalgesia and tolerance is an active area of study that offers some promise that the cellular mechanisms of tolerance might be circumvented. Wang et al. (2005) and Terner et al. (2006) demonstrated a significant attenuation in opioid tolerance when low-dose naltrexone was added to a morphine regimen in rats. A recent randomized controlled trial (RCT) in 350 osteoarthritis patients showed a statistically significant advantage in pain relief over time for patients treated with the combination of oxycodone and naltrexone over oxycodone alone, a clinical outcome that has been suggested to result from the suppression of G protein switching (Chindalore et al 2005, Crain & Shen 2000, Wang et al 2005). With further validation, this drug combination approach could be offered as a pre-emptive strategy in managing patients at risk of developing significant opioid tolerance.

The ability of CCK antagonists to prevent the development of hyperalgesia and tolerance has been suggested (King et al., 2005), largely based on studies with the CCK antagonist proglumide in animal models (Tang et al 1984, Watkins et al 1984). In several small clinical studies (Bernstein et al 1998, McCleane 2004, McCleane 1998, McCleane 2003, Price et al 1985), proglumide appeared to enhance opioid analgesia; whether the augmentation was attributed to reversal of tolerance and/or amelioration of hyperalgesia is debatable. To date, there have been no RCTs that fully document the efficacy of proglumide as a promoter of opioid analgesia. Moreover, studies in patients with documented opioid tolerance or hyperalgesia would be needed to demonstrate the putative counteractive effects of CCK antagonists on opioid-induced tolerance and hyperalgesia. Thus additional research is needed before CCK antagonists can be recommended in clinical practice (McCleane, 2004).

Blockade of the NMDA receptor has been shown to reduce opioid-induced hyperalgesia and retard opioid tolerance development in both animal models and human case reports (Celerier et al 2000, Clark & Kalan 1995, Davis & Inturrisi 1999, Eilers et al 2001, Elliott et al 1994, Gorman et al 1997, Haley et al 1990, Mao et al 1995, Mercadante 1996). However, one recent RCT in chronic pain patients failed to demonstrate a reduction in hyperalgesia or tolerance after three months of concurrent treatment with morphine and dextromethorphan (an NMDA receptor antagonist) compared with with morphine alone (Galer et al., 2005). Methadone, a mu agonist which also is an NMDA receptor antagonist, has been examined as an agent that can potentially prevent tolerance and hyperalgesia (Morley, 1998). Several clinical reports indicate that rotation to methadone from other opioids enhances analgesia (Benitez del Rosario et al 2004, Quigley 2004, Vigano et al 1996). In contrast, enhanced pain sensitivity in opioid addicts who are receiving methadone maintenance therapy is well documented (Compton et al 2001, Doverty et al 2001, Mao 2006). Thus, the role for methadone in the setting of hyperalgesia awaits further research.

Ongoing investigations to further define the variants of genes encoding the mu opioid receptor and on the key proteins involved in receptor desensitization and down-regulation are intriguing. If there were a simple way to test for these genetic differences in patients in the future, clinicians might have a more rational approach to optimal drug selection and drug rotation in opioid therapy.

Clinical strategies to prevent or manage hyperalgesia start with early identification of the problem. Hyperalgesia should be suspected whenever repeated dose escalation fails to provide the expected analgesic effects or when there is an unexplained pain exacerbation after an upward titration of opioid. The index of suspicion is higher if the increased pain is consistent with hyperesthesia or allodynia and other obvious causes such as disease progression or acute insult are ruled out. Hyperalgesia should be treated by reducing dose or eliminating the offending opioid. Theoretically, a reduction in the opioid dose with or without adding a replacement opioid or a gradual rotation to an alternate opioid would result in a decrease in pain. As with opioid tolerance, no RCTs exist demonstrating the superiority of one opioid over another in avoiding hyperalgesia.

Future Directions and Summary

The molecular mechanisms underlying opioid tolerance and opioid-induced hyperalgesia are being investigated in research laboratories throughout the world. Based on the research accomplished to date, it appears that these two phenomena may be related but also have distinct features. Future scientific efforts will be directed at deepening our understanding of how adaptive responses by multiple neural systems work together to counteract the analgesic efficacy of commonly used opioids. Future pharmaceutical development will focus on blocking the facilitatory mechanisms that produce these adaptive changes in the endogenous nociceptive and antinociceptive systems in response to continual exposure to an opioid analgesic. Development of diagnostic tests for biomarkers or genotypes that will allow identification of the opioid best suited to an individual patient's profile seems attainable within the not-too-distant future.

References

    Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104:570–587.
    Arden JR, Segredo V, Wang Z, Lameh J, Sadee W. Phosphorylation and agonist-specific intracellular trafficking of an epitope-tagged mu-opioid receptor expressed in HEK 293 cells. Journal of Neurochemistry. 1995;65:1636–1645.
    Benitez del Rosario MA, Feria M, Salinas-Martin A, Martinez-Castillo LP, Martin-Ortega JJ. Opioid switching from transdermal fentanyl to oral methadone in patients with cancer pain. Cancer. 2004;101:2866–2873.
    Bergen AW, Kokoszka J, Peterson R, Long JC, Virkkunen M, Linnoila M, et al.. Mu opioid receptor gene variants: lack of association with alcohol dependence. Molecular Psychiatry. 1997;2:490–494.
    Bernstein ZP, Yucht S, Battista E, Lema M, Spaulding MB. Proglumide as a morphine adjunct in cancer pain management. Journal of Pain & Symptom Management. 1998;15:314–320.
    Bohn LM, Lefkowitz RJ, Caron MG. Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice. Journal of Neuroscience. 2002;22:10494–10500.
    Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 1999;286:2495–2498.
    Bond C, LaForge KS, Tian M, Melia D, Zhang S, Borg L, et al.. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proceeding of the National Academies of Science of the United States of America. 1998;95:9608–9613.
    Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, et al.. Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effect of ketamine. Anesthesiology. 2000;92:465–472.
    Chavkin C, Goldstein A. Reduction in opiate receptor reserve in morphine tolerant guinea pig ilea. Life Sciences. 1982;31:1687–1690.
    Chavkin C, Goldstein A. Opioid receptor reserve in normal and morphine-tolerant guinea pig ileum myenteric plexus. Proceeding of the National Academies of Science of the United States of America. 1984;81:7253–7257.
    Chindalore VL, Craven RA, Yu KP, Butera PG, Burns LH, Friedmann N. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex. Journal of Pain. 2005;6:392–399.
    Clark JL, Kalan GE. Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient. Journal of Pain & Symptom Management. 1995;10:310–314.
    Collin E, Poulain P, Gauvain-Piquard A, Petit G, Pichard-Leandri E. Is disease progression the major factor in morphine "tolerance" in cancer pain treatment?. Pain. 1993;55:319–326.
    Compton MA. Cold-pressor pain tolerance in opiate and cocaine abusers: correlates of drug type and use status. Journal of Pain & Symptom Management. 1994;9:462–473.
    Compton P, Charuvastra VC, Ling W. Pain intolerance in opioid-maintained former opiate addicts: effect of long-acting maintenance agent. Drug & Alcohol Dependence. 2001;63:139–146.
    Crain SM, Shen KF. Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability. Pain. 2000;84:121–131.
    Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. Journal of Pharmacol Exp Ther. 1999;289:1048–1053.
    De Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. Journal of Pain Symptom & Management. 1995;10:378–384.
    Dourish CT, Hawley D, Iversen SD. Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718. European Journal of Pharmacology. 1988;147:469–472.
    Doverty M, White JM, Somogyi AA, Bochner F, Ali R, Ling W. Hyperalgesic responses in methadone maintenance patients. Pain. 2001;90:91–96.
    Drake R, Longworth J, Collins JJ. Opioid rotation in children with cancer. Journal of Palliative Medicine. 2004;7:419–422.
    Duttaroy A, Yoburn BC. The effect of intrinsic efficacy on opioid tolerance. Anesthesiology. 1995;82:1226–1236.
    Eilers H, Philip LA, Bickler PE, McKay WR, Schumacher MA. The reversal of fentanyl-induced tolerance by administration of "small-dose" ketamine. Anesthesia & Analgesia. 2001;93:213–214.
    Elliott K, Hynansky A, Inturrisi CE. Dextromethorphan attenuates and reverses analgesic tolerance to morphine. Pain. 1994;59:361–368.
    Estfan B, LeGrand SB, Walsh D, Lagman RL, Davis MP. Opioid rotation in cancer patients: pros and cons. Oncology (Williston Park). 2005;19:511–516.
    Ferguson SS, Zhang J, Barak LS, Caron MG. Role of beta-arrestins in the intracellular trafficking of G-protein–coupled receptors. Advances in Pharmacology. 1998;42:420–424.
    Finn AK, Whistler JL. Endocytosis of the mu opioid receptor reduces tolerance and a cellular hallmark of opiate withdrawal. Neuron. 2001;32:829–839.
    Foley K. Changing concepts of tolerance to opioids: what the cancer patient has taught us. In: Chapman CR, Foley KM editor. Current and emerging issues in cancer pain: research and practice. New York: Raven Press; 1993;p. 331–350.
    Galer BS, Lee D, Ma T, Schlagheck T. MorphiDex (morphine sulfate/dextromethorphan hydrobromide combination) in the treatment of chronic pain: three multicenter randomized, double-blind, controlled clinical trials fail to demonstrate enhanced opioid analgesia or reduction in tolerance. Pain. 2005;115:284–295B., N..
    Gardell LR, King T, Ossipov MH, Rice KC, Lai J, Vanderah TW, et al.. Opioid receptor–mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neuroscience Letters. 2006;396:44–49.
    Gardell LR, Wang R, Burgess SE, Ossipov MH, Vanderah TW, Malan TP, et al.. Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. Journal of Neuroscience. 2002;22:6747–6755.
    Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the noncompetitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neuroscience Letters. 1997;223:5–8.
    Haley JE, Sullivan AF, Dickenson AH. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Research. 1990;518:218–226.
    Hirota T, Ieiri I, Takane H, Sano H, Kawamoto K, Aono H, et al.. Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine therapy. Drug Metabolism & Disposition. 2003;31:677–680.
    Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain—a systematic review of randomized controlled trials. Pain. 2006;126:91–101.
    Indelicato RA, Portenoy RK. Opioid rotation in the management of refractory cancer pain. Journal of Clinical Oncology. 2002;20:348–352.
    Ivarsson M, Neil A. Differences in efficacies between morphine and methadone demonstrated in the guinea pig ileum: a possible explanation for previous observations on incomplete opioid cross-tolerance. Pharmacology & Toxicology. 1989;65:368–371.
    King T, Ossipov MH, Vanderah TW, Porreca F, Lai J. Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance?. Neurosignals. 2005;14:194–205.
    Kloke M, Rapp M, Bosse B, Kloke O. Toxicity and/or insufficient analgesia by opioid therapy: risk factors and the impact of changing the opioid (A retrospective analysis of 273 patients observed at a single center). Support Care in Cancer. 2000;8:479–486.
    Lauretti GR, Lima IC, Reis MP, Prado WA, Pereira NL. Oral ketamine and transdermal nitroglycerin as analgesic adjuvants to oral morphine therapy for cancer pain management. Anesthesiology. 1999;90:1528–1533.
    Li T, Zhu ZH, Liu X, Hu X, Zhao J, Sham PC, et al.. Association analysis of polymorphisms in the DRD4 gene and heroin abuse in Chinese subjects. American Journal of Medical Genetics. 2000;96:616–621.
    Lotsch J, Skarke C, Grosch S, Darimont J, Schmidt H, Geisslinger G. The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics. 2002;12:3–9.
    Lotsch J, Zimmermann M, Darimont J, Marx C, Dudziak R, Skarke C, et al.. Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?. Anesthesiology. 2002;97:814–819.
    Luttrell LM, Lefkowitz RJ. The role of beta-arrestins in the termination and transduction of G-protein–coupled receptor signals. Journal of Cell Science. 2002;115:455–465.
    Lynch ME. A review of the use of methadone for the treatment of chronic noncancer pain. Pain Research & Management. 2005;10:133–144.
    Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends in Neuroscience. 1995;18:22–29.
    Mansour A, Khachaturian H, Lewis ME, Akil H, Watson SJ. Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain. Journal of Neuroscience. 1987;7:2445–2464.
    Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2002;100:213–217.
    Mao J. Opioid-induced abnormal pain sensitivity. Current Pain & Headache Reports. 2006;10:67–70.
    Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. Journal of Neuroscience. 1994;14:2301–2312.
    Mao J, Price DD, Mayer DJ. Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain. Pain. 1995;61:353–364.
    Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters: implications in morphine tolerance and abnormal pain sensitivity. Journal of Neuroscience. 2002;22:8312–8323.
    McCleane GJ. Cholecystokinin antagonists a new way to improve the analgesia from old analgesics?. Current Pharmaceutical Design. 2004;10:303–314.
    McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain. Anesthesia & Analgesia. 1998;87:1117–1120.
    McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine. Clinical Journal of Pain. 2003;19:200–201.
    McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, Chew PW, et al.. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. Journal of Pain. 2003;4:231–256.
    Mercadante S. Ketamine in cancer pain: an update. Palliative Medicine. 1996;10:225–230.
    Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. Cancer. 1999;86:1856–1866.
    Morley JS. Opioid rotation: does it have a role?. Palliative Medicine. 1998;12:464–466.
    Moulin DE, Ling GS, Pasternak GW. Unidirectional analgesic cross-tolerance between morphine and levorphanol in the rat. Pain. 1988;33:233–239.
    Noble F, Cox BM. Differential desensitization of mu- and delta- opioid receptors in selected neural pathways following chronic morphine treatment. British Journal of Pharmacology. 1996;117:161–169.
    Ossipov MH, Lai J, King T, Vanderah TW, Porreca F. Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure. Biopolymers. 2005;80:319–324.
    Pasternak GW. Incomplete cross tolerance and multiple mu opioid peptide receptors. Trends in Pharmacological Sciences. 2001;22:67–70.
    Perry SJ, Lefkowitz RJ. Arresting developments in heptahelical receptor signaling and regulation. Trends in Cell Biology. 2002;12:130–138.
    Price DD, von der Gruen A, Miller J, Rafii A, Price C. Potentiation of systemic morphine analgesia in humans by proglumide, a cholecystokinin antagonist. Anesthesia & Analgesia. 1985;64:801–806.
    Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews. 2004;3:CD004847.
    Quirion R. Pain, nociception and spinal opioid receptors. Progress in Neuro-psychopharmacology & Biological Psychiatry. 1984;8:571–579.
    Quirion R, Zajac JM, Morgat JL, Roques BP. Autoradiographic distribution of mu and delta opiate receptors in rat brain using highly selective ligands. Life Sciences. 1983;33(Suppl 1):227–230.
    Raehal KM, Bohn LM. Mu opioid receptor regulation and opiate responsiveness. AAPS Journal. 2005;7:E587–E591.
    Ross JR, Riley J, Quigley C, Welsh KI. Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients. Oncologist. 2006;11:765–773.
    Ross JR, Rutter D, Welsh K, Joel SP, Goller K, Wells AU, et al.. Clinical response to morphine in cancer patients and genetic variation in candidate genes. Pharmacogenomics Journal. 2005;5:324–336.
    Saeki S, Yaksh TL. Suppression of nociceptive responses by spinal mu opioid agonists: effects of stimulus intensity and agonist efficacy. Anesthesia & Analgesia. 1993;77:265–274.
    Sander T, Gscheidel N, Wendel B, Smolka M, Rommelspacher H, Schmidt LG, et al. Human mu-opioid receptor variation and alcohol dependence. AlcoholismClinical & Experimental Research. 1998;22:2108–2110.
    Shen KF, Crain SM. Cholera toxin-A subunit blocks opioid excitatory effects on sensory neuron action potentials indicating mediation by Gs-linked opioid receptors. Brain Research. 1990;525:225–231.
    Sim-Selley LJ, Selley DE, Vogt LJ, Childers SR, Martin TJ. Chronic heroin self-administration desensitizes mu opioid receptor–activated G-proteins in specific regions of rat brain. Journal of Neuroscience. 2000;20:4555–4562.
    Sim LJ, Selley DE, Dworkin SI, Childers SR. Effects of chronic morphine administration on mu opioid receptor–stimulated [35S]GTPgammaS autoradiography in rat brain. Journal of Neuroscience. 1996;16:2684–2692.
    Sjogren P, Thunedborg LP, Christrup L, Hansen SH, Franks J. Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories. Acta Anaesthesiologica Scandinavica. 1998;42:1070–1075.
    Sosnowski M, Yaksh TL. Differential cross-tolerance between intrathecal morphine and sufentanil in the rat. Anesthesiology. 1990;73:1141–1147.
    Tang J, Chou J, Iadarola M, Yang HY, Costa E. Proglumide prevents and curtails acute tolerance to morphine in rats. Neuropharmacology. 1984;23:715–718.
    Terman GW, Jin W, Cheong YP, Lowe J, Caron MG, Lefkowitz RJ, et al.. G-Protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal. British Journal of Pharmacology. 2004;141:55–64.
    Terner JM, Barrett AC, Lomas LM, Negus SS, Picker MJ. Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains. Pain. 2006;122:90–101.
    Thomsen AB, Becker N, Eriksen J. Opioid rotation in chronic nonmalignant pain patients (A retrospective study). Acta Anaesthesiologica Scandinavica. 1999;43:918–923.
    Town T, Abdullah L, Crawford F, Schinka J, Ordorica PI, Francis E, et al. Association of a functional mu-opioid receptor allele (+118A) with alcohol dependency. American Journal of Medical Genetics. 1999;88:458–461.
    Van Bockstaele EJ, Colago EE, Cheng P, Moriwaki A, Uhl GR, Pickel VM. Ultrastructural evidence for prominent distribution of the mu-opioid receptor at extrasynaptic sites on noradrenergic dendrites in the rat nucleus locus coeruleus. Journal of Neuroscience. 1996;16:5037–5048.
    Vanderah TW, Gardell LR, Burgess SE, Ibrahim M, Dogrul A, Zhong CM, et al.. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. Journal of Neuroscience. 2000;20:7074–7079.
    Vanderah TW, Suenaga NM, Ossipov MH, Malan TP, Lai J, Porreca F. Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. Journal of Neuroscience. 2001;21:279–286.
    Vigano A, Fan D, Bruera E. Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators. Pain. 1996;67:115–119.
    Wang HY, Friedman E, Olmstead MC, Burns LH. Ultra-low-dose naloxone suppresses opioid tolerance, dependence and associated changes in mu opioid receptor–G protein coupling and Gbetagamma signaling. Neuroscience. 2005;135:247–261.
    Watkins LR, Kinscheck IB, Mayer DJ. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science. 1984;224:395–396.
    White PF. The changing role of nonopioid analgesic techniques in the management of postoperative pain. Anesthesia & Analgesia. 2005;101(5 Suppl):S5–S22.
    Xu XJ, Wiesenfeld-Hallin Z, Hughes J, Horwell DC, Hokfelt T. CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat. British Journal of Pharmacology. 1992;105:591–596.
    Yabaluri N, Medzihradsky F. Down-regulation of mu-opioid receptor by full but not partial agonists is independent of G protein coupling. Molecular Pharmacology. 1997;52:896–902.
    Yoburn BC, Gomes BA, Rajashekara V, Patel C, Patel M. Role of G(i)alpha2-protein in opioid tolerance and mu-opioid receptor downregulation in vivo. Synapse. 2003;47:109–116.