ADJUVANT ANALGESICS

Adjuvant analgesics (co-analgesics) are drugs that were developed for clinical uses other than pain but are used as an analgesic in select circumstances. The following table describes common adjuvant analgesics.

ROUTES OF ANALGESIC ADMINISTRATION

Analgesics can be administered by many routes. Each has advantages and disadvantages as well as indications and contraindications. The overriding considerations are effectiveness and safety. The table below lists some of the most common routes for the administration of analgesic drugs.

CANNABIS (MEDICAL MARIJUANA)

More than two thirds of the states, including Oregon, and the District of Columbia have legalized cannabis for medical treatments. However, federal law continues to prohibit use of cannabis or its derivatives for any purpose. This means that people may be arrested and charged with possession even in states where marijuana use is legal (UGA, 2020; NIDA, 2020a; ASA, 2021).

Under the Controlled Substances Act (CSA), cannabis is classified as a Schedule 1 drug. This means that the federal government views cannabis as highly addictive and that it has no medical value. Doctors may not prescribe cannabis for medical use under federal law, although they can “recommend” its use under the First Amendment (Stonebraker, 2022).

Mechanism of Action

Marijuana is a greenish-gray mixture of the dried flowers of the plant Cannabis sativa. The main psychoactive chemical in marijuana responsible for the intoxicating effects people experience is delta-9-tetrahydrocannabinol (THC). THC’s chemical structure is similar to anandamide, an endogenous cannabinoid, and because of this similarity, it is able to attach to and activate cannabinoid receptors in brain areas that influence pleasure, memory, thinking, and concentration (hippocampus and orbitofrontal cortex); and balance, posture, coordination, and reaction time (cerebellum and basal ganglia). THC, acting through the cannabinoid receptors, also activates the brain’s reward system to release dopamine at levels higher in response to pleasurable behaviors than those in response to other stimuli.

The other chemical from the marijuana plant that is of medical importance is cannabidiol (CBD), thought to be useful in reducing pain and in controlling epileptic seizures. The therapeutic effects of CBD are as an anticonvulsant, antipsychotic, anxiolytic, neuroprotective, sleep-promoting, and anti-inflammatory agent.

CBD, however, does not cause intoxication or euphoria (the “high”) that comes from THC because it does not affect the same receptors as THC. CBD influences the body to use its own endocannabinoids more effectively by inhibiting absorption by the body of the endogenous cannabinoid anandamide, which is associated with regulating pain. Increased levels of anandamide in the blood may reduce the amount of pain a person experiences. CBD also reduces anxiety by changing the shape of the GABA-A receptor in a way that amplifies the natural calming effect of GABA (NIDA, 2020a; Mlost et al., 202; Project CBD, 2022).

CBD is also used for the treatment of epilepsy. The exact mechanism in which CBD creates anticonvulsant effects is not known, but it possesses affinity for multiple targets resulting in functional modulation of neuronal excitability relevant to diseases such as epilepsy (Gray & Whalley, 2020).

FDA-Approved Medical Marijuana Analgesic Formulations

Whether or not the use of marijuana has therapeutic benefits that outweigh its health risks is still unresolved, but marijuana-based medications have been approved or are undergoing clinical trials. Currently the FDA has approved dronabinol (Mariol, Syndros) and nabilone (Cesamet) for relief of chronic nerve-related pain. Nabiximols (Sativest), a mouth spray for treating spasticity and neuropathic pain, is undergoing trials (UGA, 2020; ASA, 2021).

Nonpharmacologic Interventions

Evidence-based nonpharmacologic therapies are safe when correctly administered and can be effective components of comprehensive pain management that can reduce the need for opioids. Nonpharmacologic therapies can be the sole intervention, or they can be combined with other treatments. Nonpharmacologic interventions include physical, psychological, and mind-body modalities.

PHYSICAL MODALITIES

Physical modalities for relief of pain refer to any therapeutic medium that uses the transmission to or through the patient of thermal, electrical, acoustic, radiant, or mechanical energy.

Thermal Modalities (Heat and Cold)

Cold (cryotherapy) is often the first treatment applied to new injuries. Cold causes vasoconstriction, which slows blood flow and leakage of fluid from capillaries into surrounding tissue spaces and reduces bruising, swelling, inflammation, and muscle spasms. Cold slows down the pain messages transmitted to the brain and numbs tissue, acting as a local anesthetic.

Cold therapy can be applied via cold compresses, chemical cold packs, ice packs, immersion or soaking in cold water, massaging the area with an ice cube or ice pack, cold air and vapocoolant sprays, and manual and electric cold compression units. More recently, whole-body cryotherapy has been used for persistent pain in patients with rheumatological conditions; more research is needed to understand the effect on the body and its relation to pain (Physiopedia, 2022b).

Thermal modalities include superficial and deep heat. Heat may facilitate tissue healing, relax skeletal muscles, and decrease spasms and pain. Superficial heat (thermotherapy) is the use of an agent that causes temperature increase and subsequent physiological changes to the superficial layers of the skin, fat, tissues, blood vessels, muscles, nerves, tendons, ligaments, and joints. Superficial heat penetration is usually less than 1 cm into the skin and subcutaneous tissue.

Heat therapy promotes pain relief, vasodilation, increased metabolism, and elasticity of connective tissues, and is used for subacute to chronic conditions. Commonly used superficial heat modalities include hot packs, heat wraps, heating pads, hydrotherapy, steam baths, saunas, paraffin bath, infrared, ultrasound, and fluid therapy (Seidel et al., 2021).

Deep heat is produced when energy is converted into heat as it passes through body tissues. Deep heat can penetrate 3 cm to 5 cm or more without overheating underlying subcutaneous tissue or skin (Hoenig & Cary, 2021). (See also “Acoustic Modalities” below.)

Manual Modalities

Massage is the use of touch or force to areas and tissues for therapeutic purposes. Therapeutic massage involves the application of hands or elbows with the intention of solving a physical problem. Research supports the benefits of massage therapy for pain management, decreasing anxiety and depression, and reducing pain intensity in patients undergoing surgical procedures. Massage reduces pain by stimulating A-beta fibers, resulting in closing of the “gate” to impulses from the periphery, and also stimulates the release of endorphins.

Types of massage include:

• Acupressure: Application of pressure to acupuncture points
• Deep-tissue: Massage to reduce pain and inflammation
• Rolfing and myofascial release: More aggressive techniques that direct force into dysfunctional muscle and fascial tissue
• Neuromuscular therapy: A technique that releases trigger points within tight muscles
• Reflexology: Based on a system of points on the hands, feet, and ears that correspond to other parts of the body; similar in theory to acupressure, applying pressure to these points to stimulate the flow of energy, thus helping to release pain or blockages throughout the body
• Reiki: Use of light touch designed to work with the body’s energy
• Whirlpool: Water massage to decrease muscle tension, improve circulation, and relieve pain
• Swedish: The most common type of massage, to decrease muscle tension, pain, stress, and depression
  (Madore, 2022; AMTA, 2022)

Manipulation therapy is an evidence-based practice involving the application of pressure to the spine or other parts of the body to adjust and correct alignment for the treatment of musculoskeletal pain. Such techniques are commonly used to improve pain and function by osteopathic physicians, chiropractors, and physical therapists. Spinal manipulation, for example, is often recommended for acute, subacute, and chronic low back pain as well as osteoarthritis. It has also been found beneficial for neck pain, cervicogenic headache, sports injuries, and prophylaxis of migraine (PPM, 2019).

Acupuncture

Acupuncture involves placing thin needles into targeted areas of the body to ease chronic pain. According to traditional Chinese medicine, the body has patterns of energy (chi) flow. Fine needles are positioned at specific locations on the body to correct or maintain this flow. Modern medicine emphasizes how acupuncture needles stimulate nerve and muscle cells, reducing the sensation of pain and releasing the body’s endorphins. In support of this theory, there is evidence that opioid antagonists block the analgesic effects of acupuncture. Acupuncture needles can be moved or turned once they are in place, and mild electrical pulses are sometimes used between two needles (electro-acupuncture) to expand the area of pain relief (Mayo Clinic, 2022; Ahn, 2020).

Electro-Physical Agents

Electrotherapy is used to treat a range of chronic pain conditions by directing mild electric current to underlying structures.

Transcutaneous electrical nerve stimulation (TENS) is a commonly used device designed specifically for pain relief. TENS provides a low-voltage electrical current through the skin to sensory nerve fibers, producing numbness or tingling sensations that “mask” or “override” sensations of pain. The impulses from TENS fill the nerve pathways and prevent the transmission of pain signals to the brain. It may also stimulate nerves to produce endorphins, which may block the perception of pain. TENS is most commonly used to treat conditions involving muscle, joint, or bone, such as osteoarthritis, fibromyalgia, bursitis, and back and neck pain.

Although TENS may help relieve pain for some people, its effectiveness has not been proven. Many studies have been done on TENS, but most have been small or not well designed. For this reason, some experts claim that TENS can give short-term pain relief but that long-term relief has not been proven (URMC, 2022).

Interferential stimulation is more complex than TENS. It uses dual-frequency stimulation to create circuits that cross over each other to produce maximum pain signal interference at the treatment target site.

Percutaneous electric nerve stimulation (PENS) therapy uses thin needle electrodes that pierce the skin and get closer to nerve endings or muscle than does TENS therapy. PENS therapy does not destroy the affected nerves but makes them less sensitive to pain signals. It is often used if TENS therapy is unsuccessful and to treat diabetic peripheral neuropathy.

Pulse electromagnetic field stimulation (PEMF) therapy uses short bursts of low-level electromagnetic radiation to stimulate nerve or muscle. This radiation works with the body’s natural magnetic field to help increase electrolytes and ions, which naturally influences electrical changes on a cellular level and influences cellular metabolism. This combines with the body’s own recovery processes to help relieve chronic pain (Williams, 2021).

Iontophoresis allows medication to be delivered into and through the skin to a painful area without having to be injected or taken orally. Liquid medication is placed on a patch that is then applied to the painful area. A device, similar to a battery, is then attached to the patch, and the medication is delivered by a mild electrical current. Iontophoresis has been used successfully to anesthetize an area of skin with lidocaine and to treat bursitis, plantar fasciitis, or tendonitis with anti-inflammatory drugs. Although evidence is limited, studies to date indicate this modality may generally be no more effective than placebo (NLM, 2022b; Hoenig & Cary, 2021).

Acoustic Modalities

Therapeutic ultrasound is a form of mechanical energy. The ultrasound device converts electrical energy to high-frequency sound waves that penetrate deeply into muscle, nerve, bone, and connective tissues. The waves vibrate cell molecules and cause friction, which creates heat. Ultrasound can be focused on tissues deep within the body without affecting other tissues close to the surface. It can be used to treat a wide range of health problems but is most commonly used for problems in muscle tissue. The heating effect of ultrasound helps heal muscle pain and reduce chronic inflammation. Currently, there is ongoing debate as to the effectiveness of this modality (Brennan, 2021; Murphy, 2020).

Shortwave diathermy (SWD) produces deep heating by converting high-frequency, alternating electromagnetic energy to thermal energy (friction). Diathermy heats more deeply than hot packs and can heat a larger area than ultrasound. SWD can be either pulsed or continuous. Pulsed shortwave diathermy is used for patients with some acute and subacute conditions, and it prevents tissue temperature from increasing too quickly or too high. Continuous shortwave diathermy increases subcutaneous tissue temperature, and its use is generally limited to chronic conditions. It is usually applied for 20 minutes at the maximum tolerable dose and is used most commonly for short-term musculoskeletal pain relief. SWD penetrates bone and does not pose a risk of periosteal burning.

Microwave diathermy (MWD) does not penetrate as deeply as shortwave diathermy and can be focused more easily than can shortwave diathermy. Both SWD and MWD can create hotspots. MWD is useful in the treatment of traumatic and rheumatic conditions affecting superficial muscles, ligaments, and small superficial joints (Seidel et al., 2021).

Phonophoresis uses ultrasound’s high-frequency sound wave to drive a medication into the tissues by increasing cell permeability for deep heat. A topical anti-inflammatory agent is blended into the ultrasound gel and applied to the skin over the treatment area, and the ultrasound waves carry it into the tissues to reduce inflammation and also provide the benefits of therapeutic heat and vibration (Hoenig & Cary, 2021).

Vibroacoustic therapy (VAT) involves using musical sound waves to aid and facilitate in the relaxation response. VAT causes tissue to resonate, which results in physical changes such as increased blood circulation and metabolism and reduction in sympathetic activity. It is commonly used for anxiety/stress, muscular tension, fatigue, pain management, and other conditions such as fibromyalgia, tinnitus, and Parkinson’s disease (Seidel et al., 2021).

Light Therapy

Light therapy includes low-level laser therapy (LLLT), also known as cold laser therapy, and ultraviolet light (UV). UV light therapy uses the electromagnetic wavelength between X-ray and visible light to bring about a biochemical response in tissue to reduce pain. LLLT uses low-powered laser light to produce this effect.

Photons in light temporarily create a neural blockage (as an anesthetic) by decreasing mitochondrial membrane potential and ATP, which decreases the inflammatory neuropeptides. LLLT is believed to affect fibroblast function, accelerate connective tissue repair, and may have an anti-inflammatory effect by reducing prostaglandin synthesis. UV light may have similar biological effects. Both forms of light therapy are used to decrease acute and chronic pain and inflammation, stimulate collagen metabolism, and promote wound healing (Seidel et al., 2021).

Interventional Pain Modalities

When noninvasive strategies are insufficient, patients may be offered various invasive options that include:

• Injection therapies
• Soft tissue and joint injections may be used for conditions such as bursitis, tendonitis, arthritis, osteoarthritis, and carpal tunnel syndrome. Trigger point injections are used for musculoskeletal pain. Anti-inflammatory medications (corticosteroids) are the most common drugs to use in injections and often are combined with pain relievers such as lidocaine.
• Nerve blocks provide temporary pain relief by injecting a local anesthetic to temporarily interrupt peripheral nerve transmission of pain. Nerve blocks may be given in the facet joints of the spine, hip joint, sacroiliac joint, coccyx, shoulder, elbow, hand, knee, ankle, foot, and occipital, saphenous, and pudendal nerves.
• Neurolytic blocks produce analgesia by destroying afferent neural pathways or sympathetic structures involved in pain transmission by injecting a material that damages the nerve (e.g., water, hypertonic saline, phenol, or alcohol).
• Epidural steroid injections send steroids directly to an inflamed nerve root; two or three injections are required for maximum relief.
• Botulinum toxin injections block chemical signals from nerves that cause muscle to contract. They are used for cervical dystonia and treatment of chronic migraine.
• Prolotherapy is used to treat joint and muscle pain. It is sometimes called regenerative injection or proliferation therapy. It involves injecting a sugar or saline substance into a joint or muscle, where it acts as an irritant, resulting in immune cells and other chemicals being sent to the area, thus starting the body’s natural healing process.
• Platelet-rich plasma (PRP) injections are used for a range of conditions, including musculoskeletal pain and injuries. Platelets contain growth factors that can trigger cell reproduction and stimulate tissue regeneration. An increased concentration of growth factors has been shown to stimulate or speed up the healing process and decrease pain.
• Radiofrequency ablation involves using X-ray guidance to insert a needle with an electrode at the tip, which is then heated in order to temporarily “turn off” a nerve’s ability to transmit pain signals to the brain. Other names are radiofrequency rhizotomy and neuroablation.
• Cryotherapy ablation uses medical-grade nitrous oxide to generate extremely cold temperatures to selectively destroy nerve tissue and prevent transmission of the pain signal to the brain.
• Intrathecal pump implants provide potent medications directly to the source of pain. This is a type of neuromodulation that interrupts pain signals to the brain. It involves a small pump implanted under the skin that is programmed to deliver a specific amount of medication. The pump requires refilling every few months.
• Spinal cord stimulator. A device is implanted under the skin and sends a mild electric current to the spinal cord. Thin wires carry current from a pulse generator to the nerve fibers of the spinal cord. When turned on, the device stimulates nerves in the area where the pain is felt. Pain is reduced because the electrical pulses modify and mask the pain signal.
• Intradiscal electrothermal therapy (IDET) is a minimally invasive technique for treating discogenic low back pain. It involves the percutaneous threading of a flexible catheter into a disc under fluoroscopic guidance. The catheter heats the posterior annulus of the disc, causing contraction of collagen fibers and destruction of afferent nociceptors.
• Dry needling is a physical therapy technique (where allowed by state law) that is part of a larger treatment plan for musculoskeletal pain. Dry needling involves penetrating the skin with a thin filiform needle and stimulating underlying myofascial trigger points and muscular connective tissues that cannot be manually palpable. The goal is to release or inactivate trigger points to relieve pain or improve range of motion.
  (Mayo Clinic, 2021; UCSF, 2022; Brennan, 2021; Johns Hopkins Medicine, 2022;Thiyagarajah, 2020; APTA, 2021)

PSYCHOLOGICAL MODALITIES

Cognitive-Behavioral Therapy (CBT)

One of the most common types of psychotherapy used in pain management is cognitive-behavioral therapy. CBT can be described as the “gold standard” psychological treatment for persons with a wide range of pain issues. It can be used alone or in conjunction with medical or interdisciplinary rehabilitation treatments. Currently, CBT is the prevailing psychological treatment for individuals with chronic pain issues.

CBT practice varies but often includes relaxation training, setting and working toward behavioral goals, behavioral activation, guidance in activity pacing, problem-solving training, and cognitive restructuring. The role of CBT is to help patients recognize the emotional and psychological factors that influence pain perception and the behaviors associated with having pain (Physiopedia, 2022c).

Acceptance and Commitment Therapy (ACT)

The basic premise of acceptance and commitment therapy is for patients to shift their primary focus from reducing or eliminating pain to fully engaging in their lives. The goal of the therapy is to help patients accept whatever discomfort exists, both physical and emotional, while continuing to live their lives according to their values. ACT applies six core treatment processes to create psychological flexibility (Glasofer, 2021).

MIND-BODY TECHNIQUES

Biofeedback

Biofeedback is the use of instrumentation to mirror psychophysiologic processes, such as blood pressure, heart rate, and skin temperature, of which an individual normally is unaware and which may be brought under voluntary control. Researchers aren’t exactly sure how or why biofeedback works, but they do know that it promotes relaxation, which can help relieve many conditions related to stress (Watson, 2020).

Relaxation Therapies

Relaxation therapies have been found helpful in the management of chronic headaches and other types of chronic pain. Relaxation encourages reduction in muscle tension, resulting in a decrease in pain intensity. There are a number of practices—such as progressive relaxation, autogenic training, guided imagery, self-hypnosis, and deep-breathing exercises—and the goal is similar for all: to produce the body’s natural relaxation response, characterized by slower breathing, lower blood pressure, and a feeling of increased well-being (NCCIH, 2021).

Hypnosis

Hypnosis is a procedure involving cognitive processes in which the patient is guided by a health professional to respond to suggestions for changes in perceptions, sensations, thoughts, feelings, and behaviors. It involves learning how to use the mind and thoughts to manage emotional distress, unpleasant physical symptoms, and certain habits or behaviors. Hypnosis can provide analgesia, reduce stress, relieve anxiety, improve sleep, improve mood, and reduce the need for opioids. It can also enhance the effectiveness of other forms of relaxation therapies and biofeedback for pain (Cosio & Lin, 2020).

Distraction

The brain has a limited capacity for attention, and there are only so many things it can concentrate on at the same time. Pain sensations compete for attention with all the other things going on. Just how much attention the brain gives each thing depends on a number of factors, including:

• How long the person has been dealing with pain
• Current mood
• Propensity to anxiety, rumination, and catastrophizing

Diverting attention (distracting) from feelings and thoughts of pain is a well-researched pain coping strategy. Mental distractions actually block pain signals from the body before they ever reach the brain. Distraction is shifting attention away from pain or painful stimuli to something more engaging or enjoyable. Research supports the use of distraction for acute pain among infants and children, with less consistent evidence for adolescents and adults (Stanford Health Care, 2021; Keane, 2021).

Mindfulness-Based Interventions

Mindfulness-based interventions (e.g., meditation) have been found to have significant effects on chronic pain, yet the mechanisms underlying these effects are not well understood.

The most widely used is mindfulness-based stress reduction (MBSR), which has been found to be effective in reducing the adverse impact of chronic pain. MBSR can increase the ability to tolerate or withstand distressing emotional or physical states and selectively alter the unpleasantness of pain. MBSR uses a combination of body awareness, mindfulness meditation, and movement to help people become focused on and accepting of the present moment (Cosio & Demyan, 2021).

Virtual Reality (VR)

Virtual reality therapies have been shown to effectively distract patients who suffer from chronic and acute pain. Virtual reality is a computer-generated world that simulates real-life experiences through senses and perception. An individual using VR equipment is able to look around the artificial world, move around in it, and interact with virtual features or even thoughts. This world is commonly created by using a VR headset that consists of a head-mounted display with a small screen positioned in front of the eyes, stereo sound, and sensors.

Virtual reality provides immersive experiences that absorb more of the brain’s attention. With fewer mental resources left to process pain signals, people perceive less pain. VR causes a reduction of the electrical signals through which neurons communicate. Further validation tests of EEG and investigation on VR effects are needed to better understand how our brain acts while immersed in a virtual world (VirtualTimes, 2021).

Virtual reality has also been shown to benefit children by reducing the fear and anxiety they experience before a procedure. Children tend to be more cooperative when engaged in VR, with less movement, less fear, and lower pain scores (Children’s Hospital Los Angeles, 2021).

Mirror Therapy (MT)

Mirror therapy is a rehabilitation therapy in which a mirror is placed between the arms or legs so that the image of a moving, nonaffected limb gives the illusion of normal movement in the affected limb. Mirror therapy exploits the brain’s preference to prioritize visual feedback over somatosensory/proprioceptive feedback concerning limb position. The reflection “tricks” the brain into thinking there are two healthy limbs.

Mirror therapy has been used to manage phantom leg or arm pain, reduce pain following a stroke, and for patients with a complex regional pain syndrome (Physiopedia, 2022d).

Using a mirror, the brain is “tricked” into seeing two limbs. (Source: © Sköld et al., 2011.)

Yoga

Yoga is a mind-body and exercise practice that helps relieve chronic pain. Yoga has many of the same benefits as mindfulness practice due to the common focus on breath, body, and present-moment awareness. There are different types of yoga, with the most evidence of benefit being shown through Iyengar yoga, hatha yoga, and Viniyoga.

It is not fully understood how yoga helps with pain, but emerging evidence suggests it might help people more effectively control how they think and feel, both mentally and physically. It may also work by improving muscle flexibility, promoting relaxation, reducing inflammation, or increasing the release of pain-relieving endorphins, as well as improving confidence and the sense of self-control. Most evidence for the use of yoga is in those with chronic back pain, arthritis, headaches/migraines, irritable bowel syndrome, fibromyalgia, and carpal tunnel syndrome (DHWA, 2021).

Tai Chi and Qigong

Tai chi and qigong are forms of traditional Chinese exercise that incorporate the concepts of two opposing forces—yin and yang. Both exercises are based on the idea and core principle that increasing energy in the body, known as chi, through gentle and repeated movements can enhance a person’s well-being. Pain or sickness is believed to occur when the flow of chi is blocked or when yin and yang energies are out of balance. The joints are seen as gates that control the flow of chi and that can be opened by using slow and gentle swaying movements, deep breathing, and mental focus.

The exact mechanism behind relief of chronic pain through the practice of qigong or tai chi isn’t fully known. Some researchers theorize that pain relief is achieved by eliminating muscular tension through deep relaxation or boosting endorphins. Others believe that the exercises may affect the autonomic nervous system, increasing parasympathetic tone, which is related to a relaxed state of body with a reduction in stress hormones (Marks, 2022; Winchester Hospital, 2022).

Evaluating the Effectiveness of Interventions

There are multiple outcome measures required to adequately assess the pain experience and how it has been modified by pain management interventions. The outcome of pain management is done by assessing:

• The degree of analgesic effect in comparison to the patient’s baseline
• The time to onset of the analgesic effect and the time to maximum reduction in pain intensity
• The duration of the analgesic effect
• Measures of physical functioning
• Measures of emotional functioning
• Secondary effects related to the treatment
  (Edward, 2021)