In examining the published studies on opioid-induced hyperalgesia (OIH), Reznikov "et al" criticize the methodologies employed on both humans and animals as being far-removed from the typical regimen and dosages of pain patients in the real world. They also note that some OIH studies were performed on drug addicts in methadone rehabilitation programs, and that such results are very difficult to generalize and apply to medical patients in chronic pain. In contrast, a study of 224 chronic pain patients receiving 'commonly-used' doses of oral opioids, in more typical clinical scenarios, found that the opioid-treated patients actually experienced no difference in pain sensitivity when compared to patients on non-opioid treatments. The authors conclude that opioid-induced hyperalgesia may not be an issue of any significance for normal, medically-treated chronic pain patients at all.

Opioid-induced hyperalgesia has also been criticized as overdiagnosed among chronic pain patients, due to poor differential practice in distinguishing it from the much more common phenomenon of opioid tolerance. The misdiagnosis of common opioid tolerance (OT) as opioid-induced hyperalgesia (OIH) can be problematic as the clinical actions suggested by each condition can be contrary to each other. Patients misdiagnosed with OIH may have their opioid dose mistakenly decreased (in the attempt to counter OIH) at times when it is actually appropriate for their dose to be increased or rotated (as a counter to opioid tolerance).

The suggestion that chronic pain patients who are diagnosed as experiencing opioid-induced hyperalgesia ought to be completely withdrawn from opioid therapy has also been met with criticism. This is not only because of the uncertainties surrounding the diagnosis of OIH in the first place, but because of the viability of rotating the patient between different opioid analgesics over time. Opioid rotation is considered a valid alternative to the reduction or cessation of opioid therapy, and multiple studies demonstrate the rotation of opioids to be a safe and effective protocol.

Opioid-induced hyperalgesia or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia is a phenomenon associated with the long-term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.

Tolerance, another condition that can arise from prolonged exposure to opioids, can often be mistaken for opioid-induced hyperalgesia and vice-versa, as the clinical presentation can appear similar. Although tolerance and opioid-induced hyperalgesia both result in a similar need for dose escalation to receive the same level of effect to treat pain, they are nevertheless caused by two distinct mechanisms. The similar net effect makes the two phenomena difficult to distinguish in a clinical setting. Under chronic opioid treatment, a particular individual's requirement for dose escalation may be due to tolerance, opioid-induced hyperalgesia, or a combination of both. In tolerance, there is a lower sensitivity to opioids, which occurs via two major theories: decreased receptor activation (desensitization of antinociceptive mechanisms), and opioid receptor down-regulation (internalization of membrane receptors). In opioid-induced hyperalgesia, sensitization of pronociceptive mechanisms occurs, resulting in a decrease in the pain threshold, or allodyna. Identifying the development of hyperalgesia is of great clinical importance since patients receiving opioids to relieve pain may paradoxically experience more pain as a result of treatment. Whereas increasing the dose of opioid can be an effective way to overcome tolerance, doing so to compensate for opioid-induced hyperalgesia may worsen the patient's condition by increasing sensitivity to pain while escalating physical dependence.

The phenomenon is common among palliative care patients following a too rapid escalation of opioid dosage.

The risk of chemotherapy-induced nausea and vomiting varies based on the type of treatment received, as well as several outside factors. Some types of chemotherapy are more prone to causing nausea and vomiting than others. Some chemotheraputic agents may not cause nausea and vomiting on their own, but may when used in combination with other agents. Regimens that are linked to a high incidence (90% or higher) of nausea and vomiting are referred to as "highly emetogenic chemotherapy", and those causing a moderate incidence (30–90%) of nausea and vomiting are referred to as "moderately emetogenic chemotherapy".

Some highly emetogenic agents and chemotherapy regimens include:

- Cisplatin

- Dacarbazine

- Cyclophosphamide (>1500 mg/m)

- Carmustine (>250 mg/m)

- Mechlorethamine

- Streptozocin

- ABVD

- MOPP/COPP/BEACOPP

- CBV

- VIP

- BEP

- AC

Some moderately emetogenic agents and regimens include:

- Carboplatin

- Methotrexate

- Doxorubicin/Adriamycin

- Docetaxel

- Paclitaxel

- Etoposide

- Ifosfamide

- Cyclophosphamide (≤1500 mg/m)

- CHOP/CHOP-R

Besides the type of treatment, personal factors may put a patient at greater risk for CINV. Other risk factors include:

- Female sex

- Patient age (under 55 years old)

- History of light alcohol use

- History of previous CINV

- History of nausea and vomiting during pregnancy

- History of motion sickness

- Anxiety or depression

- Anticipation of CINV

Hyperalgesia is induced by platelet-activating factor (PAF) which comes about in an inflammatory or an allergic response. This seems to occur via immune cells interacting with the peripheral nervous system and releasing pain-producing chemicals (cytokines and chemokines).

One unusual cause of focal hyperalgesia is platypus venom.

Long-term opioid (e.g. heroin, morphine) users and those on high-dose opioid medications for the treatment of chronic pain, may experience hyperalgesia and experience pain out of proportion to physical findings, which is a common cause for loss of efficacy of these medications over time. As it can be difficult to distinguish from tolerance, opioid-induced hyperalgesia is often compensated for by escalating the dose of opioid, potentially worsening the problem by further increasing sensitivity to pain. Chronic hyperstimulation of opioid receptors results in altered homeostasis of pain signalling pathways in the body with several mechanisms of action involved. One major pathway being through stimulation of the nociceptin receptor, and blocking this receptor may therefore be a means of preventing the development of hyperalgesia.

Stimulation of nociceptive fibers in a pattern consistent with that from inflammation switches on a form of amplification in the spinal cord, long term potentiation. This occurs where the pain fibres synapse to pain pathway, the periaqueductal grey. Amplification in the spinal cord may be another way of producing hyperalgesia.

The release of proinflammatory cytokines such as interleukin-1 by activated leukocytes triggered by lipopolysaccharides, endotoxins and other signals of infection also increases pain sensitivity as part of sickness behavior, the evolved response to illness.

Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. Conditioning studies have established that it is possible to experience a learned hyperalgesia of the latter, diffuse form.

The focal form is typically associated with injury, and is divided into two subtypes:

- "Primary hyperalgesia" describes pain sensitivity that occurs directly in the damaged tissues.

- "Secondary hyperalgesia" describes pain sensitivity that occurs in surrounding undamaged tissues.

Opioid-induced hyperalgesia may develop as a result of long-term opioid use in the treatment of chronic pain. Various studies of humans and animals have demonstrated that primary or secondary hyperalgesia can develop in response to both chronic and acute exposure to opioids. This side effect can be severe enough to warrant discontinuation of opioid treatment.

Drugs in systemic circulation have a certain concentration in the blood, which serves as a surrogate marker for how much drug will be delivered throughout the body (how much drug the rest of the body will "see"). There exists a minimum concentration of drug within the blood that will give rise to the intended therapeutic effect (minimum effective concentration, MEC), as well as a minimum concentration of drug that will give rise to an unintended adverse drug event (minimum toxic concentration, MTC). The difference between these two values is generally referred to as the therapeutic window. Different drugs have different therapeutic windows, and different people will have different MECs and MTCs for a given drug. If someone has a very low MTC for a drug, they are likely to experience adverse effects at drug concentrations lower than what it would take to produce the same adverse effects in the general populace; thus, the individual will experience significant toxicity at a dose that is otherwise considered "normal" for the average person. This individual will be considered "intolerant" to that drug.

There are a variety of factors that can affect the MTC, which is often the subject of clinical pharmacokinetics. Variations in MTC can occur at any point in the ADME (absorption, distribution, metabolism, and excretion) process. For example, a patient could possess a genetic defect in a drug metabolizing enzyme in the cytochrome P450 superfamily. While most individuals will possess the effective metabolizing machinery, a person with a defect will have a difficult time trying to clear the drug from their system. Thus, the drug will accumulate within the blood to higher-than-expected concentrations, reaching a MTC at a dose that would otherwise be considered normal for the average person. In other words, in a person that is intolerant to a medication, it is possible for a dose of 10 mg to "feel" like a dose of 100 mg, resulting in an overdose—a "normal" dose can be a "toxic" dose in these individuals, leading to clinically significant effects.

There is also an aspect of drug intolerance that is subjective. Just as different people have different pain tolerances, so too do people have different tolerances for dealing with the adverse effects from their medications. For example, while opioid-induced constipation may be tolerable to some individuals, other people may stop taking an opioid due to the unpleasantness of the constipation even if it brings them significant pain relief.

Allodynia (Ancient Greek "" "állos" "other" and "" "odúnē" "pain") refers to central pain sensitization (increased response of neurons) following normally non-painful, often repetitive, stimulation. Allodynia can lead to the triggering of a pain response from stimuli which do not normally provoke pain. Temperature or physical stimuli can provoke allodynia, which may feel like a burning sensation, and it often occurs after injury to a site. Allodynia is different from hyperalgesia, an extreme, exaggerated reaction to a stimulus which is normally painful.

Allodynia is a clinical feature of many painful conditions, such as neuropathies, complex regional pain syndrome, postherpetic neuralgia, fibromyalgia, and migraine. Allodynia may also be caused by some populations of stem cells used to treat nerve damage including spinal cord injury. Static mechanical allodynia is a paradoxical painful hypoaesthesia, one etiology of which is lesions of A-beta fibers.

Usually, acute pain is generated from an obvious cause and is expected to last for only a few days or weeks. It is usually managed with medication and non-pharmacological treatment to provide comfort. Acute pain is an indication for needed assessment, treatment and prevention. While a child is experiencing pain, physiological changes occur that can further jeopardize healing and recovery. Unrelieved pain can cause alkalosis and hypoxemia that result from rapid, shallow breathing. This shallow breathing then leads to the accumulation of fluid in the lungs, taking away to the ability to cough. Dangerously enough, this can prevent the secretions from being expelled. Pain can cause an increase in blood pressure and heart rate, creating great stress on the heart. Additionally, pain increases the release of anti-inflammatory steroids that reduce the ability to fight infection. These same steroids that are released increase the metabolic rate and impact healing. Another harmful outcome of acute pain is an increase in sympathetic effects such as the inability to urinate. Such aches can even slow down the gastrointestinal system.

Inadequate pain management in children can lead to psycho-social consequences. Disinterest in food, apathy, sleep problems, anxiety, avoidance of discussions about health, fear, hopelessness and powerlessness are just some of the many. Other consequences can be extended hospital stays, high readmission rates and a longer recovery. On the other hand, the American Association of Pediatrics describes pain with immunizations as "The pain associated with the majority of immunizations is minor.".

Examples of harmful consequences due to unrelieved pain:

- infants with a higher than average heel sticks can have poor cognitive and motor function

- distress caused by needle-sticks make medical treatments later on more difficult

- children who have experienced invasive procedures often times develop post-traumatic stress (PST)

- boys circumcised without anesthesia were found to have greater distress than uncircumcised boys.

- severe pain as a child is associated with higher reports of pain in adults

Acute pain can be expected in response to many if not most invasive procedures. Anticipation of pain and distress can guide a pre-treatment, pain-prevention plan based on past reports of pain associated with the medical procedure. Individuals with technical expertise and experience are more likely to minimize the pain as much as possible. Preparation before a procedure with information that is understood by children and parents decrease distress. Parents can contribute to the improvement of this issue by learning effective methods/ways to comfort their child. Types of procedures determine the use of deep sedation or anesthesia. In some cases, the best method to prevent and relieve pain is by building self-esteem. Suggested cognitive behavioral strategies are: imagery, relaxation, a massage, heat compression, calm adults, a quiet environment, and confident explanations by providers. Since distress can be addressed and controlled, some children benefit from the opportunity for self-regulation. Pain reduction during invasive procedures is closely linked to controlling distress. Treating distress even for minor or uncomplicated procedures, likes venipuncture can be implemented.

Intolerance to analgesics, particularly NSAIDs, is relatively common. It is thought that a variation in the metabolism of arachidonic acid is responsible for the intolerance. Symptoms include chronic rhinosinusitis with nasal polyps, asthma, gastrointestinal ulcers, angioedema, and urticaria.

Risk factors for opioid overdose include opioid dependence, injecting opioids, using high doses of opioids, and use together with alcohol or benzodiazepines. The risk is particularly high following detoxification. Dependence on prescription opioids can occur from their use to treat chronic pain.

Opioid use disorder can develop as a result of self-medication, though this is controversial. Scoring systems have been derived to assess the likelihood of opiate addiction in chronic pain patients.

According to position papers on the treatment of opioid dependence published by the United Nations Office on Drugs and Crime and the World Health Organization, care providers should not treat opioid use disorder as the result of a weak character or will. Additionally, detoxification alone does not constitute adequate treatment.

Permanent brain damage may occur due to cerebral hypoxia or opioid-induced neurotoxicity.

Physical dependence is a physical condition caused by chronic use of a tolerance forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certain medications such as benzodiazepines, opioids, antiepileptics and antidepressants, as well as the recreational misuse of drugs such as alcohol, opioids, and benzodiazepines. The higher the dose used, the greater the duration of use, and the earlier age use began are predictive of worsened physical dependence and thus more severe withdrawal syndromes. Acute withdrawal syndromes can last days, weeks or months. Protracted withdrawal syndrome, also known as post-acute-withdrawal syndrome or "PAWS", is a low-grade continuation of some of the symptoms of acute withdrawal, typically in a remitting-relapsing pattern, often resulting in relapse and prolonged disability of a degree to preclude the possibility of lawful employment. Protracted withdrawal syndrome can last for months, years, or depending on individual factors, indefinitely. Protracted withdrawal syndrome is noted to be most often caused by benzodiazepines. To dispel the popular misassociation with addiction, physical dependence to medications is sometimes compared to dependence on insulin by persons with diabetes.

Treatment for physical dependence depends upon the drug being withdrawn and often includes administration of another drug, especially for substances that can be dangerous when abruptly discontinued or when previous attempts have failed. Physical dependence is usually managed by a slow dose reduction over a period of weeks, months or sometimes longer depending on the drug, dose and the individual. A physical dependence on alcohol is often managed with a cross tolerant drug, such as long acting benzodiazepines to manage the alcohol withdrawal symptoms.

Conditions of fatigue correlate positively with increased alcohol consumption.

Cancer pain is managed differently in children. Clinicians treating cancer pain can come from a variety of disciplines or specialties. Typically, medical history, physical examinations, age and overall health of the child is evaluated. The type of cancer may influence decisions about pain management. The extent of the cancer, the tolerance of the child to specific medications, procedure or therapies is also taken into account. The preferences of the parent or caregiver contribute to the determining of the best way to treat cancer pain. For cancer pain, opioids are helpful and can be taken orally. The side effects are: constipation, fatigue, and disorientation. Others are given IV, subcutaneous, or trans-dermal. Switching medications may be necessary at times. Dosing for children is based upon studies with adults or short-term studies. Children can develop opioid tolerance where larger doses are needed to have the same effect. When resistance to opioids develop, the pain responsiveness is reset and pain increases. Tolerance is likely to develop in younger children.

Cocaine can be snorted, swallowed, injected, or smoked. Most deaths due to cocaine are accidental but may also be the result of body packing or stuffing with rupture in the gastrointestinal tract. Use of cocaine causes tachyarrhythmias and a marked elevation of blood pressure (hypertension), which can be life-threatening. This can lead to death from acute myocardial infarction, respiratory failure, stroke, cerebral hemorrhage, or heart failure. Cocaine overdose may result in hyperthermia as stimulation and increased muscular activity cause greater heat production. Heat loss is also inhibited by the cocaine-induced vasoconstriction. Cocaine and/or associated hyperthermia may cause muscle cell destruction (rhabdomyolysis) and myoglobinuria resulting in renal failure. Individuals with cocaine overdose should be transported immediately to the nearest emergency department, preferably by ambulance in case cardiac arrest occurs en route. According to the National Institute on Drug Abuse, approximately 5000 deaths occur annually in the US due to cocaine overdose.

Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects – for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never even used before.

The hypothesized causes of meth mouth are a combination of MA side effects and lifestyle factors which may be present in users:

- Dry mouth (xerostomia)

- Clenching and grinding of the teeth (bruxism)

- Infrequent oral hygiene

- Frequent consumption of sugary, fizzy drinks

- Caustic nature of methamphetamine

The dental effects of long-term methamphetamine use are often attributed to its effects on saliva. The reduction in saliva increases the likelihood of dental caries, enamel erosion, and periodontal disease. Although it is clear that use of the drug decreases saliva, the mechanism by which it does so is unclear. One theory is that the drug causes vasoconstriction (narrowing of the blood vessels) in salivary glands, decreasing salivary flow. This constriction is thought to be due to the activation of alpha-adrenergic receptors by both methamphetamine itself and norepinephrine, the levels of which are dramatically increased by methamphetamine use. These factors can be compounded by dehydration, which occurs in many methamphetamine users after drug-induced increases in metabolism. The characteristics of the saliva produced during use of the drug, which includes high protein content, may also contribute to the sensation of dry mouth.

Long-term methamphetamine use can cause parafunctional habits, routine actions of a body part that are different than their common use, which can result in tooth wear and exacerbate periodontal diseases. One such habit that may affect the development of meth mouth is bruxism, particularly as the drug's effects wane and stereotypy occurs, a phase that is often referred to as "tweaking". This bruxism may be due to a drug-induced increase in monoamines. Other behaviors of long-term methamphetamine users that may cause or accelerate the symptoms of meth mouth are the failure to pay attention to oral hygiene and excessive food intake during binges, especially sugary foods; the drug's users often report strong cravings for sugar and consume large amounts of high-sugar beverages. The altered mental state that accompanies methamphetamine use lasts longer than that of some other common drugs, increasing the amount of time the user engages in drug-induced behavior.

Hydrochloric acid is used in methamphetamine's manufacturing process, but academic reviews have not supported the idea that the acid contributes to dental decay. Speculation that oral consumption of the drug causes tooth decay by raising the acidity of users' mouths is also unsupported. Meth mouth is generally most severe in users who inject the drug, rather than those who smoke, ingest or inhale it.

Inhalation of an agonist for the beta-2 adrenergic receptor, such as Salbutamol, Albuterol (US), is the most common treatment for asthma. Polymorphisms of the beta-2 receptor play a role in tachyphylaxis. Expression of the Gly-16 allele (glycine at position 16) results in greater receptor downregulation by endogenous catecholamines at baseline compared to Arg-16. This results in a greater single-use bronchodilator response in individuals homozygous for Arg-16 compared to Gly-16 homozygotes. However, with regular beta-2 agonist use, asthmatic Arg-16 individuals experience a significant decline in bronchodilator response. This decline does not occur in Gly-16 individuals. It has been proposed that the tachyphylactic effect of regular exposure to exogenous beta-2 agonists is more apparent in Arg-16 individuals because their receptors have not been downregulated prior to agonist administration.

Low doses of alcohol (one beer) appear to increase total sleep time and reduce awakening during the night. The sleep-promoting benefits of alcohol dissipate at moderate and higher doses of alcohol. Previous experience with alcohol also influences the extent to which alcohol positively or negatively affects sleep. Under free-choice conditions, in which subjects chose between drinking alcohol or water, inexperienced drinkers were sedated while experienced drinkers were stimulated following alcohol consumption. In insomniacs, moderate doses of alcohol improve sleep maintenance.

CRPS can occur at any age with the average age at diagnosis being 42. It affects both men and women; however, CRPS is three times more frequent in females than males.

CRPS affects both adults and children, and the number of reported CRPS cases among adolescents and young adults has been increasing, with a recent observational study finding an incidence of 1.16/100,000 among children in Scotland.

Good progress can be made in treating CRPS if treatment is begun early, ideally within three months of the first symptoms. If treatment is delayed, however, the disorder can quickly spread to the entire limb, and changes in bone, nerve, and muscle may become irreversible. The prognosis is not always good. Johns Hopkins Hospital reports that 77% of sufferers have spreads from the original site or flares in other parts of the body. The limb, or limbs, can experience muscle atrophy, loss of use, and functionally useless parameters that require amputation. RSD/CRPS will not "burn itself out", but if treated early, it is likely to go into remission. Once one is diagnosed with Complex Regional Pain Syndrome, the likelihood of it resurfacing after going into remission is significant. It is important to take precautions and seek immediate treatment upon any injury.

Cocaine increases alertness, feelings of well-being, euphoria, energy, competence, sociability, and sexuality. Common side effects include anxiety, increased temperature, paranoia, restlessness, and teeth grinding. With prolonged use, the drug can cause insomnia, anorexia, tachycardia, hallucinations, and paranoid delusions. Possible lethal side effects include rapid heartbeat, abnormal heart rhythms, tremors, convulsions, markedly increased core temperature, renal failure, heart attack, stroke and heart failure.

Depression with suicidal ideation may develop in heavy users. Finally, a loss of vesicular monoamine transporters, neurofilament proteins, and other morphological changes appear to indicate a long-term damage to dopamine neurons. Chronic intranasal usage can degrade the cartilage separating the nostrils (the septum nasi), which can eventually lead to its complete disappearance.

Studies have shown that cocaine usage during pregnancy triggers premature labor and may lead to abruptio placentae.