Does long-term use of painkillers and opioids (narcotic analgesics) decrease pain tolerance?

From the Guidelines

Yes, long-term use of painkillers and opioids can decrease pain tolerance through a phenomenon called opioid-induced hyperalgesia (OIH), as supported by the most recent and highest quality study 1. This occurs when patients taking opioids like oxycodone, hydrocodone, morphine, or fentanyl for extended periods (typically months to years) paradoxically become more sensitive to pain. Common medications associated with this effect include OxyContin, Vicodin, MS Contin, and Duragesic patches. The body adapts to chronic opioid exposure by altering pain signaling pathways in the nervous system, essentially amplifying pain signals over time. This is different from tolerance, where patients need increasing doses for the same pain relief. Some key points to consider include:

• OIH can be expressed during ongoing opioid administration as an increase in pain intensity over time
• It can also manifest as diffuse pain (or pain spreading to other locations)
• Or as an increase in pain sensation to external stimuli such as touch
• The true relationship between opioid tolerance and OIH remains uncertain, and the two may not always overlap, as noted in 1 and 1
• Management typically involves gradual tapering of opioids under medical supervision, rotation to different pain medications, or incorporating non-opioid pain management strategies like NSAIDs, anticonvulsants (gabapentin, pregabalin), physical therapy, and cognitive behavioral therapy
• The underlying mechanism involves changes to NMDA receptors, glial cell activation, and altered neurotransmitter systems that collectively make the nervous system more reactive to pain signals, as discussed in 1 and 1.

From the FDA Drug Label

Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects Physical dependence is a physiological state in which the body adapts to the drug after a period of regular exposure, resulting in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug.

Long-term use of painkillers and opioids can lead to tolerance, which means that the body gets used to the drug and needs higher doses to achieve the same effect.

• Tolerance is a sign that the body has adapted to the opioid.
• Physical dependence can also occur, resulting in withdrawal symptoms when the drug is stopped or reduced. The FDA drug label does not directly answer whether pain tolerance decreases as a result of taking painkillers and opioids, but it does indicate that tolerance to the analgesic effect can occur, which may be perceived as a decrease in pain tolerance 2, 2, 3.

From the Research

Long-term Use of Painkillers and Opioids

• The long-term use of painkillers and opioids can lead to a decrease in pain tolerance, as the body adapts to the constant presence of these substances 4, 5.
• Opioids, in particular, can cause analgesic tolerance, which requires a dose increase to maintain a sufficient analgesic effect, and can also lead to physical dependence 5.
• The development of tolerance is connected to side effects such as respiratory depression, and it is highly desirable to avoid or at least attenuate the development of tolerance 5.

Mechanisms Underlying Tolerance

• The mechanisms underlying tolerance are complex and not fully understood, but recent studies suggest that receptor down-regulation is not the main mechanism in vivo 5.
• A desensitization on the basis of receptor decoupling, receptor internalization, and increased alternative coupling to stimulatory G-proteins have been demonstrated 5.
• Functional antagonism of the opioid effects, mediated by the activation of NMDA receptors, up-regulation of adenylyl cyclase, and nitric oxide synthase, seems to be clinically most important 5.

Clinical Strategies to Minimize Tolerance

• Drugs blocking these mechanisms, such as alpha2-adrenoreceptor agonists and NMDA antagonists, have been used to minimize tolerance development during opioid treatment 5.
• Clinical strategies such as opioid rotation and multimodal analgesia, i.e., the simultaneous application of several analgetics of different types, have proven to be successful approaches 5.
• The use of non-opioid alternatives, such as NSAIDs and acetaminophen, can also be effective in managing pain and reducing the risk of tolerance and dependence 6, 7, 8.