The withdrawal syndrome from heroin may begin starting from within 6 to 24 hours of discontinuation of sustained use of the drug; however, this time frame can fluctuate with the degree of tolerance as well as the amount of the last consumed dose. Symptoms may include: sweating, malaise, anxiety, depression, persistent and intense penile erection in males (priapism), extra sensitivity of the genitals in females, general feeling of heaviness, cramp-like pains in the limbs, yawning and lacrimation, sleep difficulties, cold sweats, chills, severe muscle and bone aches not precipitated by any physical trauma, nausea and vomiting, diarrhea, goose bumps, cramps, and fever. In an addict with a high tolerance, heroin withdrawal may even lead to death.

Many addicts also complain of a painful condition, the so-called "itchy blood", which often results in compulsive scratching that causes bruises and sometimes ruptures the skin, leaving scabs. Abrupt termination of heroin use causes muscle spasms in the legs of the user (restless leg syndrome). Users taking the "cold turkey" approach (withdrawal without using symptom-reducing or counteractive drugs) are more likely to experience the negative effects of withdrawal in a more pronounced manner.

Two general approaches are available to ease the physical part of opioid withdrawal. The first is to substitute a longer-acting opioid such as methadone or buprenorphine for heroin or another short-acting opioid and then slowly taper the dose.

In the second approach, benzodiazepines such as diazepam (Valium) may temporarily ease the often extreme anxiety of opioid withdrawal. The most common benzodiazepine employed as part of the detox protocol in these situations is oxazepam (Serax). Benzodiazepine use must be prescribed with care because benzodiazepines have a great addiction potential, and many opioid addicts also use other central nervous system depressants including barbiturates. Also, though unpleasant, opioid withdrawal seldom has the potential to be fatal, whereas complications related to withdrawal from benzodiazepines, barbiturates and alcohol (such as epileptic seizures, cardiac arrest, and delirium tremens) can prove hazardous and are potentially fatal. Many symptoms of opioid withdrawal are due to rebound hyperactivity of the sympathetic nervous system, which can be suppressed with clonidine (Catapres), a centrally-acting alpha-2 agonist primarily used to treat hypertension.

Buprenorphine is one of the substances most recently licensed for the substitution of illegal opioids. Being a partial opioid agonist/antagonist, it develops a lower grade of tolerance than heroin or methadone due to the so-called ceiling effect. It also has less severe withdrawal symptoms than heroin when discontinued abruptly, which should never be done without proper medical supervision. It is usually administered every 24-48 hrs. Buprenorphine is a kappa-opioid receptor antagonist. This gives the drug an anti-depressant effect, increasing physical and intellectual activity. [citation needed] Buprenorphine also acts as a partial agonist at the same μ-receptor where illicit opioids like heroin exhibit their action. Due to its effects on this receptor, all patients whose tolerance is above a certain level are unable to obtain any "high" from other opioids during buprenorphine treatment except for very high doses.

Researchers at Johns Hopkins University have been testing a sustained-release "depot" form of buprenorphine that can relieve cravings and withdrawal symptoms for up to six weeks. A sustained-release formulation would allow for easier administration and adherence to treatment, and reduce the risk of diversion or misuse.

Methadone is another μ-opioid agonist most often used to substitute for heroin in treatment for heroin addiction. Compared to heroin, methadone is well (but slowly) absorbed by the gastrointestinal tract and has a much longer duration of action of approximately 24 hours. Thus methadone maintenance avoids the rapid cycling between intoxication and withdrawal associated with heroin addiction. In this way, methadone has shown some success as a "less harmful substitute"; despite bearing about the same addiction potential as heroin, it is recommended for those who have repeatedly failed to complete withdrawal or have recently relapsed. As of 2005, the μ-opioid agonist buprenorphine is also being used to manage heroin addiction, being a superior, though still imperfect and not yet widely known alternative to methadone. Methadone, since it is longer-acting, produces withdrawal symptoms that appear later than with heroin, but usually last considerably longer and can in some cases be more intense. Methadone withdrawal symptoms can potentially persist for over a month, compared to heroin where significant physical symptoms would subside in 4 days.

Two opioid antagonists are known: naloxone and the longer-acting naltrexone. These two medications block the effects of heroin, as well as the other opioids at the receptor site. Recent studies have suggested that the addition of naloxone and naltrexone may improve the success rate in treatment programs when combined with the traditional therapy.

The University of Chicago undertook preliminary development of a heroin vaccine in monkeys during the 1970s, but it was abandoned. There were two main reasons for this. Firstly, when immunised monkeys had an increase in dose of x16, their antibodies became saturated and the monkey had the same effect from heroin as non-immunised monkeys. Secondly, until they reached the x16 point immunised monkeys would substitute other drugs to get a heroin-like effect. These factors suggested that immunised human addicts would simply either take massive quantities of heroin, or switch to other hard drugs, which is known as cross-tolerance.

There is also a controversial treatment for heroin addiction based on a plant-derived African psychedelic drug, ibogaine. Many people travel abroad for ibogaine treatments that generally interrupt the addiction for 3 - 6 months or more in up to 80% of patients. Relapse often occurs when the person returns home to their normal environment however, where drug seeking behaviour may return in response to social and environmental cues.[citation needed] Ibogaine treatments are carried out in several countries in South America and in Europe but can be dangerous. Some addicts find the ibogaine therapy most effective when it is given several times over the course of a few months or years, but this can be very expensive. A synthetic derivative of ibogaine, 18-methoxycoronaridine is in phase 2 trials in humans as an anti-addictive drug