The Journal of Family Practice

A 36-year-old man sought treatment at our outpatient dermatology clinic for an asymptomatic penile lesion that he’d had for a month. He’d been diagnosed with human immunodeficiency virus (HIV) infection 5 years earlier, and was taking highly active antiretroviral therapy of emtricitabine 200 mg/tenofovir 300 mg daily and nevirapine 200 mg twice a day. The patient’s CD4 T-cell count was 530 cells/mm3 (normal for a nonimmunocompromised adult is 500-1200 cells/mm3) and his viral load was undetectable. He wasn’t in a committed relationship and reported having no sexual partners for many years.

Physical examination revealed an indurated, 7 mm white to pink keratotic papule with a central depression near the coronal sulcus (FIGURE). No ulcers or erosions were seen. The patient denied having urethral discharge, pain, or pruritus. During the previous week, he said he’d applied triamcinolone cream 0.1% twice daily to the area with no improvement.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The asymptomatic nature and clinical presentation of the patient’s lesion prompted us to suspect syphilis. Skin biopsy of the lesion revealed features that were consistent with syphilis and a rapid plasma reagin (RPR) was positive with a titer of 1:32, confirming our suspicions. (His RPR was checked 3 years earlier and it was nonreactive.) Despite the diagnosis, the patient continued to deny having had any recent sexual encounters.

The “great mimicker”

Syphilis infection occurs after inoculation of Treponema pallidum through microscopic breaks in the mucosal surfaces followed by attachment and invasion of spirochete into host cells. Treponemes then multiply and circulate to the regional lymph nodes and internal organs, leading to a variety of clinical manifestations based on the stage of the infection (primary, secondary, and latent/late), the time that has elapsed since inoculation, and the host’s immune response.

Syphilis is often referred to as the “great mimicker” based on its propensity to present as one of a variety of phenotypes. Syphilitic chancres often mimic other genital ulcers, including those caused by different sexually transmitted diseases such as chancroid (as a result of infection with Haemophilus ducreyi) or granuloma inguinale (Klebsiella granulomatis). Syphilitic chancres may also appear clinically similar to genital aphthous ulcers or cutaneous manifestations of herpes simplex virus.

Chancroid. While the tender ulcer of chancroid has a ragged and undermined border with a dirty gray base, the classic, nontender, syphilitic chancre has a clean base with an indurated border reminiscent of the firm quality of cartilage.¹

Granuloma inguinale presents as one or multiple nontender, friable, soft, red granulating papules that lack the firm border or clean base of the syphilitic chancre.¹

Aphthous ulcers are often soft, shallow, and tender, appearing punched-out with surrounding rims of erythema and clean, white, even bases.²

Genital herpes simplex virus is characterized by tender eroded coalescing vesicles with scalloped, soft borders, contrasted by the indurated smooth rounded border of the syphilitic chancre.¹

How syphilis affects HIV, and vice versa

HIV infection has been known to alter the natural history and presentation of syphilis, and syphilis may also impact the course and evaluation of HIV infection.³ Syphilis and other infections that lead to genital ulcers increase an individual’s propensity to acquire HIV due to the loss of the barrier function of the epithelial membrane and the production of cytokines stimulated by treponemal lipoproteins.⁴ This facilitates transmission of the virus.

Syphilis may have an atypical clinical presentation in patients who are also infected with HIV. In the typical clinical presentation of primary syphilis in an immunocompetent patient, an indolent papule develops 10 to 90 days after inoculation and subsequently ulcerates into an indurated chancre. Patients with HIV may develop multiple chancres that are larger, deeper, and more ulcerative.^4-6 Approximately one-quarter of these patients present with lesions of both primary and secondary syphilis at the time of diagnosis.⁵ However, our patient presented with a solitary painless indurated papule after years of stable and well-controlled HIV infection; this suggests that cutaneous manifestations of syphilis may have atypical clinical presentations in patients who are also infected with HIV.^5,6

What you’ll see in the secondary stage

In immunocompetent patients, secondary syphilis is characterized by fever, malaise, lymphadenopathy, moth-eaten alopecia, focal neurologic findings, condyloma lata, mucocutaneous aphthae, and a generalized papulosquamous eruption.⁷ After 3 to
12 weeks, the secondary infection spontaneously disappears and leads into the latency period, which may last years. Thirty percent of untreated patients progress from latent to tertiary syphilis.⁷ During this stage, treponemes invade the central nervous system, heart, bone, and skin, triggering vigorous host cellular immune responses and delayed-type hypersensitivity reactions.

When complicated by HIV, secondary syphilis may present along a more aggressive course, with early neurologic and ophthalmologic involvement.⁸ Patients coinfected with syphilis and HIV are also more prone to developing neurosyphilis—even after completing penicillin therapy—and a more intensive diagnostic evaluation should be considered for such patients.⁹ Higher protein levels and lower glucose levels in the cerebrospinal fluid are also reported in HIV-infected patients with syphilis,¹⁰ likely due to the weakened host immune response.

What you’ll see on the labwork

In HIV patients, syphilis may cause transient increases in viral load with decreases in the CD4 count that resolve after treatment. Like other acute infections, syphilis may cause transient increases in viral load with decreases in the CD4 count that resolve after treatment.^11-14 Also worth noting:

• RPR at titers of >1:32 and CD4 counts <350 cells/mm³ may be associated with neurosyphilis in patients with HIV.¹⁰
• High RPR titers have been linked to elevated liver function enzymes in patients with syphilis and HIV, although the clinical significance of this is
  unknown.¹⁵

Treat with penicillin

All stages of syphilis can be treated with penicillin G, a standard benzathine penicillin.¹⁶ Adult patients with primary and secondary syphilis should receive a single intramuscular dose of 2.4 million units of benzathine penicillin G.¹⁶

Our patient responded well to the recommended course of penicillin therapy and no other systemic signs of the infection were noted. He was also counseled on safe sexual practices and barrier protection.

CORRESPONDENCE
Katherine Masterpol, 955 Main Street Suite G6, Winchester, MA 01890; drkasia@gmail.com

A 36-year-old man sought treatment at our outpatient dermatology clinic for an asymptomatic penile lesion that he’d had for a month. He’d been diagnosed with human immunodeficiency virus (HIV) infection 5 years earlier, and was taking highly active antiretroviral therapy of emtricitabine 200 mg/tenofovir 300 mg daily and nevirapine 200 mg twice a day. The patient’s CD4 T-cell count was 530 cells/mm3 (normal for a nonimmunocompromised adult is 500-1200 cells/mm3) and his viral load was undetectable. He wasn’t in a committed relationship and reported having no sexual partners for many years.

Physical examination revealed an indurated, 7 mm white to pink keratotic papule with a central depression near the coronal sulcus (FIGURE). No ulcers or erosions were seen. The patient denied having urethral discharge, pain, or pruritus. During the previous week, he said he’d applied triamcinolone cream 0.1% twice daily to the area with no improvement.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The asymptomatic nature and clinical presentation of the patient’s lesion prompted us to suspect syphilis. Skin biopsy of the lesion revealed features that were consistent with syphilis and a rapid plasma reagin (RPR) was positive with a titer of 1:32, confirming our suspicions. (His RPR was checked 3 years earlier and it was nonreactive.) Despite the diagnosis, the patient continued to deny having had any recent sexual encounters.

The “great mimicker”

Syphilis infection occurs after inoculation of Treponema pallidum through microscopic breaks in the mucosal surfaces followed by attachment and invasion of spirochete into host cells. Treponemes then multiply and circulate to the regional lymph nodes and internal organs, leading to a variety of clinical manifestations based on the stage of the infection (primary, secondary, and latent/late), the time that has elapsed since inoculation, and the host’s immune response.

Syphilis is often referred to as the “great mimicker” based on its propensity to present as one of a variety of phenotypes. Syphilitic chancres often mimic other genital ulcers, including those caused by different sexually transmitted diseases such as chancroid (as a result of infection with Haemophilus ducreyi) or granuloma inguinale (Klebsiella granulomatis). Syphilitic chancres may also appear clinically similar to genital aphthous ulcers or cutaneous manifestations of herpes simplex virus.

Chancroid. While the tender ulcer of chancroid has a ragged and undermined border with a dirty gray base, the classic, nontender, syphilitic chancre has a clean base with an indurated border reminiscent of the firm quality of cartilage.¹

Granuloma inguinale presents as one or multiple nontender, friable, soft, red granulating papules that lack the firm border or clean base of the syphilitic chancre.¹

Aphthous ulcers are often soft, shallow, and tender, appearing punched-out with surrounding rims of erythema and clean, white, even bases.²

Genital herpes simplex virus is characterized by tender eroded coalescing vesicles with scalloped, soft borders, contrasted by the indurated smooth rounded border of the syphilitic chancre.¹

How syphilis affects HIV, and vice versa

HIV infection has been known to alter the natural history and presentation of syphilis, and syphilis may also impact the course and evaluation of HIV infection.³ Syphilis and other infections that lead to genital ulcers increase an individual’s propensity to acquire HIV due to the loss of the barrier function of the epithelial membrane and the production of cytokines stimulated by treponemal lipoproteins.⁴ This facilitates transmission of the virus.

Syphilis may have an atypical clinical presentation in patients who are also infected with HIV. In the typical clinical presentation of primary syphilis in an immunocompetent patient, an indolent papule develops 10 to 90 days after inoculation and subsequently ulcerates into an indurated chancre. Patients with HIV may develop multiple chancres that are larger, deeper, and more ulcerative.^4-6 Approximately one-quarter of these patients present with lesions of both primary and secondary syphilis at the time of diagnosis.⁵ However, our patient presented with a solitary painless indurated papule after years of stable and well-controlled HIV infection; this suggests that cutaneous manifestations of syphilis may have atypical clinical presentations in patients who are also infected with HIV.^5,6

What you’ll see in the secondary stage

In immunocompetent patients, secondary syphilis is characterized by fever, malaise, lymphadenopathy, moth-eaten alopecia, focal neurologic findings, condyloma lata, mucocutaneous aphthae, and a generalized papulosquamous eruption.⁷ After 3 to
12 weeks, the secondary infection spontaneously disappears and leads into the latency period, which may last years. Thirty percent of untreated patients progress from latent to tertiary syphilis.⁷ During this stage, treponemes invade the central nervous system, heart, bone, and skin, triggering vigorous host cellular immune responses and delayed-type hypersensitivity reactions.

When complicated by HIV, secondary syphilis may present along a more aggressive course, with early neurologic and ophthalmologic involvement.⁸ Patients coinfected with syphilis and HIV are also more prone to developing neurosyphilis—even after completing penicillin therapy—and a more intensive diagnostic evaluation should be considered for such patients.⁹ Higher protein levels and lower glucose levels in the cerebrospinal fluid are also reported in HIV-infected patients with syphilis,¹⁰ likely due to the weakened host immune response.

What you’ll see on the labwork

In HIV patients, syphilis may cause transient increases in viral load with decreases in the CD4 count that resolve after treatment. Like other acute infections, syphilis may cause transient increases in viral load with decreases in the CD4 count that resolve after treatment.^11-14 Also worth noting:

• RPR at titers of >1:32 and CD4 counts <350 cells/mm³ may be associated with neurosyphilis in patients with HIV.¹⁰
• High RPR titers have been linked to elevated liver function enzymes in patients with syphilis and HIV, although the clinical significance of this is
  unknown.¹⁵

Treat with penicillin

All stages of syphilis can be treated with penicillin G, a standard benzathine penicillin.¹⁶ Adult patients with primary and secondary syphilis should receive a single intramuscular dose of 2.4 million units of benzathine penicillin G.¹⁶

Our patient responded well to the recommended course of penicillin therapy and no other systemic signs of the infection were noted. He was also counseled on safe sexual practices and barrier protection.

CORRESPONDENCE
Katherine Masterpol, 955 Main Street Suite G6, Winchester, MA 01890; drkasia@gmail.com

A 36-year-old man sought treatment at our outpatient dermatology clinic for an asymptomatic penile lesion that he’d had for a month. He’d been diagnosed with human immunodeficiency virus (HIV) infection 5 years earlier, and was taking highly active antiretroviral therapy of emtricitabine 200 mg/tenofovir 300 mg daily and nevirapine 200 mg twice a day. The patient’s CD4 T-cell count was 530 cells/mm3 (normal for a nonimmunocompromised adult is 500-1200 cells/mm3) and his viral load was undetectable. He wasn’t in a committed relationship and reported having no sexual partners for many years.

Physical examination revealed an indurated, 7 mm white to pink keratotic papule with a central depression near the coronal sulcus (FIGURE). No ulcers or erosions were seen. The patient denied having urethral discharge, pain, or pruritus. During the previous week, he said he’d applied triamcinolone cream 0.1% twice daily to the area with no improvement.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The asymptomatic nature and clinical presentation of the patient’s lesion prompted us to suspect syphilis. Skin biopsy of the lesion revealed features that were consistent with syphilis and a rapid plasma reagin (RPR) was positive with a titer of 1:32, confirming our suspicions. (His RPR was checked 3 years earlier and it was nonreactive.) Despite the diagnosis, the patient continued to deny having had any recent sexual encounters.

The “great mimicker”

Syphilis infection occurs after inoculation of Treponema pallidum through microscopic breaks in the mucosal surfaces followed by attachment and invasion of spirochete into host cells. Treponemes then multiply and circulate to the regional lymph nodes and internal organs, leading to a variety of clinical manifestations based on the stage of the infection (primary, secondary, and latent/late), the time that has elapsed since inoculation, and the host’s immune response.

Syphilis is often referred to as the “great mimicker” based on its propensity to present as one of a variety of phenotypes. Syphilitic chancres often mimic other genital ulcers, including those caused by different sexually transmitted diseases such as chancroid (as a result of infection with Haemophilus ducreyi) or granuloma inguinale (Klebsiella granulomatis). Syphilitic chancres may also appear clinically similar to genital aphthous ulcers or cutaneous manifestations of herpes simplex virus.

Chancroid. While the tender ulcer of chancroid has a ragged and undermined border with a dirty gray base, the classic, nontender, syphilitic chancre has a clean base with an indurated border reminiscent of the firm quality of cartilage.¹

Granuloma inguinale presents as one or multiple nontender, friable, soft, red granulating papules that lack the firm border or clean base of the syphilitic chancre.¹

Aphthous ulcers are often soft, shallow, and tender, appearing punched-out with surrounding rims of erythema and clean, white, even bases.²

Genital herpes simplex virus is characterized by tender eroded coalescing vesicles with scalloped, soft borders, contrasted by the indurated smooth rounded border of the syphilitic chancre.¹

How syphilis affects HIV, and vice versa

HIV infection has been known to alter the natural history and presentation of syphilis, and syphilis may also impact the course and evaluation of HIV infection.³ Syphilis and other infections that lead to genital ulcers increase an individual’s propensity to acquire HIV due to the loss of the barrier function of the epithelial membrane and the production of cytokines stimulated by treponemal lipoproteins.⁴ This facilitates transmission of the virus.

Syphilis may have an atypical clinical presentation in patients who are also infected with HIV. In the typical clinical presentation of primary syphilis in an immunocompetent patient, an indolent papule develops 10 to 90 days after inoculation and subsequently ulcerates into an indurated chancre. Patients with HIV may develop multiple chancres that are larger, deeper, and more ulcerative.^4-6 Approximately one-quarter of these patients present with lesions of both primary and secondary syphilis at the time of diagnosis.⁵ However, our patient presented with a solitary painless indurated papule after years of stable and well-controlled HIV infection; this suggests that cutaneous manifestations of syphilis may have atypical clinical presentations in patients who are also infected with HIV.^5,6

What you’ll see in the secondary stage

In immunocompetent patients, secondary syphilis is characterized by fever, malaise, lymphadenopathy, moth-eaten alopecia, focal neurologic findings, condyloma lata, mucocutaneous aphthae, and a generalized papulosquamous eruption.⁷ After 3 to
12 weeks, the secondary infection spontaneously disappears and leads into the latency period, which may last years. Thirty percent of untreated patients progress from latent to tertiary syphilis.⁷ During this stage, treponemes invade the central nervous system, heart, bone, and skin, triggering vigorous host cellular immune responses and delayed-type hypersensitivity reactions.

When complicated by HIV, secondary syphilis may present along a more aggressive course, with early neurologic and ophthalmologic involvement.⁸ Patients coinfected with syphilis and HIV are also more prone to developing neurosyphilis—even after completing penicillin therapy—and a more intensive diagnostic evaluation should be considered for such patients.⁹ Higher protein levels and lower glucose levels in the cerebrospinal fluid are also reported in HIV-infected patients with syphilis,¹⁰ likely due to the weakened host immune response.

What you’ll see on the labwork

In HIV patients, syphilis may cause transient increases in viral load with decreases in the CD4 count that resolve after treatment. Like other acute infections, syphilis may cause transient increases in viral load with decreases in the CD4 count that resolve after treatment.^11-14 Also worth noting:

• RPR at titers of >1:32 and CD4 counts <350 cells/mm³ may be associated with neurosyphilis in patients with HIV.¹⁰
• High RPR titers have been linked to elevated liver function enzymes in patients with syphilis and HIV, although the clinical significance of this is
  unknown.¹⁵

Treat with penicillin

All stages of syphilis can be treated with penicillin G, a standard benzathine penicillin.¹⁶ Adult patients with primary and secondary syphilis should receive a single intramuscular dose of 2.4 million units of benzathine penicillin G.¹⁶

Our patient responded well to the recommended course of penicillin therapy and no other systemic signs of the infection were noted. He was also counseled on safe sexual practices and barrier protection.

CORRESPONDENCE
Katherine Masterpol, 955 Main Street Suite G6, Winchester, MA 01890; drkasia@gmail.com

A switch to hydromorphone 20 mg/d—the physician used the 5:1 morphine-to-hydromorphone conversion ratio, then decreased the dose by 50% to account for incomplete cross-tolerance—left Ms. G lethargic. In addition, her pain score rose to 5, and she began having difficulty swallowing the medication. Prior to the drug rotation, she was able to perform light tasks and was alert enough to interact with her family.

If Ms. G were your patient, what would be your next step?

By bypassing 
first-pass metabolism, intrathecal drug delivery provides greater pain relief at lower dosages and with fewer adverse effects than systemic delivery. Continuous intrathecal (IT) drug delivery systems have been in use for more than 30 years.¹ And, while IT administration of analgesia has become increasingly useful for patients with refractory chronic pain and spasticity, it remains an underutilized resource.² Delivered directly into the pre- and post-synaptic opioid receptors in the dorsal horn of the spinal cord, IT analgesia bypasses first-pass metabolism. The result: a higher rate of efficacy, with smaller dosages and fewer adverse effects than systemic delivery.¹

The drugs are delivered via a small battery-powered programmable pump that is implanted under the subcutaneous tissue of the abdomen and connected to a catheter tunneled to the site of spinal entry. The device must be refilled periodically—typically every one to 3 months—but this is not a difficult process. It can be done in an office setting or in the patient’s home by a specially trained visiting nurse.³

There is ample reason to consider this approach when systemic analgesics or antispasmodics fail to control pain or cause unacceptable adverse effects. So why isn’t it used more frequently? One factor may be that many primary care physicians—often the first practitioners called upon to manage these complicated cases—know too little about it.

Who is a potential candidate for IT analgesia? What medications can be administered via this route? What is the role of a family physician (FP) in coordinating and overseeing the care of a patient being treated with IT therapy? Our goals in writing this review are to address these questions.

Patient selection: Not just for cancer pain

Because of the invasive nature and high cost of implantation, intrathecal pumps are typically reserved for patients with a life expectancy of more than 6 months. FPs interested in referring patients for IT therapy have many factors to consider before consulting a pain specialist. Foremost among them are the different criteria for individuals with cancer-related pain and those with chronic nonmalignant pain.

IT analgesia for cancer pain has been shown to improve patients’ quality of life and potentially increase long-term survival due to a decrease in systemic toxicity.^4-6 An appropriate candidate is an individual who, like Ms. G, was initially responsive to systemic opioids but later developed refractory symptoms or intolerance.⁷ Because of the invasive nature and high cost of implantation, subcutaneous IT pumps are typically reserved for patients with a life expectancy of more than 6 months.⁷ But implantation may be considered for those with a shorter life expectancy if they have severe pain or cannot tolerate the adverse effects of systemic analgesia.

Noncancer pain is more complex

The use of IT analgesia in patients with chronic nonmalignant pain, such as failed back surgery syndrome, spasticity associated with multiple sclerosis, or diabetic neuropathy, is both more controversial and more complex. It is important for FPs to recognize the multidimensional nature of this type of pain, which may be complicated by physical, psychological, and behavioral factors, including the possibility of addiction.^8-11

Although IT analgesia is less subject to abuse and diversion than systemic opioids, the dependent relationship associated with a continuous delivery system makes risk stratification a necessity.¹² Psychological testing is commonly used to evaluate potential candidates for long-term IT analgesia.

Prior to placement, patients must have had a failed course of conservative pain management and have no surgical options, no medical contraindications (eg, spinal pathology or susceptibility to infection), and no evidence of active addiction.¹² A medication history is crucial, too, to identify use of anticoagulation therapy—a relative contraindication—as well as drug allergies and potential drug-drug interactions to guard against.³

An IT trial may be required

Psychological testing is commonly used to evaluate potential candidates for long-term intrathecal analgesia. It is common practice for patients to undergo an IT analgesia trial prior to implantation of a subcutaneous pump. This involves using an external pump to infuse the selected medication intrathecally and slowly titrating it according to symptoms for 2 to 3 days. During this time frame, the patient records his or her response; a reduction by more than half in VAS pain score is considered a success, indicating that the patient is an appropriate candidate for placement of the device.^3,13

Drug choices—a look at the evidence

The US Food and Drug Administration (FDA) has approved 3 medications for continuous IT delivery: morphine, ziconotide, and baclofen. But it is common practice to use alternative agents, such as other opioids, local anesthetics, or alpha 2-adrenergic agonists (TABLE).^3,14-34 

CASE  › Ms. G’s primary care physician referred her to a pain specialist, who thought she would benefit from IT analgesia. After a successful single-shot IT trial with 0.5 mg morphine, the patient underwent implantation.  The specialist chose morphine as the IT agent because of Ms. G’s history of successful pain relief with it, and because such a low dose was unlikely to be a problem for a patient with renal failure.

A month later, when she returned to the specialist to have the pump refilled, Ms. G reported a pain score of 3.

Opioids such as morphine exhibit a wider spread of analgesia when administered intrathecally, resulting in fewer adverse effects than systemic opioids.^13,35,36 The mu-opioid receptors in the dorsal horn of the spinal cord are the primary target of IT opioids.

In a multicenter randomized trial involving 200 cancer patients on opioids, Smith et al⁴ compared implantable IT drug delivery systems with comprehensive medical management. The mean VAS pain score in the IT group fell 52% vs a decline of 39% in the medical management group. 

The evidence supporting IT opioids for nonmalignant pain is not as strong. This may be due to inherent differences in pain mechanisms. In cancer pain, between 75% and 90% of pain is either nociceptive or mixed nociceptive-neuropathic; the etiology of noncancer pain is more variable.^37-39 

Although IT opioid therapy is associated with a lower incidence of adverse effects than systemic therapy, this route is not devoid of adverse effects. Opioids delivered intrathecally may still be associated with respiratory depression, constipation, urinary retention, nausea/vomiting, sweating, and hyperalgesia.³⁹ In addition, chronic opioid use suppresses the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis^14,40,41—a risk with long-term IT as well as systemic administration.¹⁴  Respiratory depression most commonly results from accidental overdosing, and patients must be monitored during initiation and dose escalation of IT opioid therapy.¹⁵

Local anesthetics. Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for patients with cancer^16-20 and noncancer pain.^21,22 Local anesthetics work via the blockade of voltage-gated sodium channels, interfering with neuron depolarization.¹⁷

Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for cancer and noncancer pain. A retrospective study in which patients with malignant pain and those with failed back surgery syndrome had bupivacaine added to their IT opioid solution found that the combination led to lower pain scores and a 23% reduction in opioid dosage.²⁰ In another retrospective review, researchers demonstrated that the coadministration of IT bupivacaine and an opioid decreased the rate of opioid dose escalation by 65% over the first year in patients with noncancer pain.²³

However, a double-blind randomized, crossover multicenter study found that in patients with chronic nonmalignant pain, the addition of bupivacaine to IT opioids failed to produce significant improvement in pain control compared with opioid use alone. Quality of life scores did improve, however, in the group receiving combination therapy.²⁴

Adverse effects of local anesthetics delivered intrathecally include numbness, paresthesias, weakness, bowel/bladder dysfunction, and neurotoxicity.^17,19,25  

Calcium channel blockers. Found in venom produced by the marine snail Conus magus, ziconotide blocks presynaptic N-type channels. It is the only calcium channel blocker used to manage chronic pain.²⁶ Several trials in patients with malignant and nonmalignant pain have shown a significant decrease in VAS pain scores compared with placebo.^25,26 In addition, a multicenter, double-blind placebo-controlled crossover study evaluating IT ziconotide for the treatment of refractory pain in 111 patients with cancer and AIDS found that the treatment group obtained significantly better pain relief than the controls (53% vs 17.5% using a VAS pain intensity score).²⁵ However, 31% of those in the treatment group experienced adverse effects, the most common of which were confusion, somnolence, and urinary retention.

Ziconotide has FDA approval only as monotherapy. But because of its high cost and adverse effect profile, it is mainly used in combination with other IT drugs.²⁷ Ziconotide increases the risk of suicide in patients with a history of depression.²⁸ The prevalence of adverse effects correlates with a higher dose, faster titration rate, and older age.^26,28

Alpha-2 adrenergic agonists. Clonidine is the only alpha-2 agonist with FDA approval for epidural use, with several studies supporting its off-label use in combination with IT therapy.^22,29 In a prospective open-label study evaluating combination IT therapy in patients with failed back surgery syndrome, 73% reported subjective ratings of good or excellent at 2-year follow-up.²² The most common adverse effects were sedation, hypotension, nausea, and dry mouth.

Gamma-aminobutyric acid (GABA) agonists. Baclofen, a GABA agonist with FDA approval for the treatment of spasticity, has been used intrathecally since the mid-1980s.³² Several studies have supported its effectiveness for this purpose.^30,42  Clinical studies have also found IT baclofen to be effective in treating conditions such as complex regional pain syndrome, central pain, and neuropathic pain secondary to failed back surgery syndrome.^31,32 In one randomized double-blind crossover trial, 7 women with complex regional pain syndrome were given bolus injections of baclofen or saline. Those treated with baclofen experienced a reduction in pain and regained function.³¹

In another trial—a double-blind placebo-controlled study of patients with multiple sclerosis and spinal cord injury comparing baclofen with placebo—those treated with baclofen showed significant reductions in dysesthetic and spasm-related pain.³² The most common adverse effects of baclofen are drowsiness, cognitive impairment, weakness, gastrointestinal complaints, and sexual dysfunction.³¹

Which patients and which drugs? An expert consensus

Due to the potential for inconsistent patient management and the use of therapies with anecdotal evidence, the Polyanalgesic Consensus Conference (PACC)—a panel of experts in IT therapy—convened in 2000, 2003, 2007, and 2011 to develop recommendations for IT therapy and an algorithm for drug selection. PACC’s list of chronic conditions for which IT should be considered includes axial low back pain, postherpetic neuralgia, spinal cord injury, spinal stenosis, pancreatitis, osteoporosis, compression fracture, and phantom limb pain, among others.

The algorithm contains separate arms for neuropathic, nociceptive, and mixed pain states. First-line agents for neuropathic pain include morphine, alone or combined with bupivacaine, and ziconotide. For nociceptive pain, morphine, hydromorphone, fentanyl, and ziconotide are all first-line agents; for mixed pain states, the appropriate choice should be based on the clinical scenario.³³

Overseeing IT pain management in primary care

Referring potential candidates for IT therapy to specialists in pain management is just the beginning. While patients typically return to the specialist for pump refills, it is important that they see their primary care physician regularly, as well. Vigilance is required of both the FP and the patient. Any sudden worsening in pain level or acute change in neurologic function must be reported to the pain specialist immediately. 

Adverse effects of medications are the most common complications

Kamran and Wright⁴³ performed a retrospective review of their practice’s Intrathecal Drug Delivery Systems database of 122 patients and found that adverse medication effects were most common, accounting for 77% of complications.

Catheter malfunctions were next, at 16%, followed by infections, at 5%.⁴³ In other studies, catheter-related complications were found to have an incidence of 15% to 25%.^44,45 Problems include kinking, breaking, leaking, and migration of the catheter. Advise patients to immediately contact their pain specialist for evaluation if they experience a sudden loss of, or change in, pain control.

Any sudden worsening in pain level or acute change in neurologic function must be reported immediately. Infectious complications, which occur infrequently, are usually limited to superficial wounds, although epidural abscesses and meningitis are possible.⁴⁶ Standard perioperative antibiotic administration helps to minimize the risk of infection. If a patient presents with signs and symptoms of an epidural abscess—back pain, fever, and variable neurologic deficits—emergent initiation of intravenous antibiotics is needed. Magnetic resonance imaging (MRI) with and without gadolinium should be obtained, as well.²²

Spinal damage. Although IT catheters are placed under fluoroscopic guidance, there is a risk of direct injury to the spinal cord; this is more common if the catheter is placed above the level of the conus medullaris. Damage to the spinal cord or exiting spinal nerves will manifest as pain, sensory loss, and/or weakness over a dermatomal distribution.⁴³

Neurologic sequelae, ranging from mild symptoms to paraplegia, can  result from the formation of a granuloma at the tip of the spinal catheter. A sudden increase in pain usually occurs prior to neurologic deterioration, thereby allowing for early detection and intervention.⁴⁷ Development of a granuloma appears to be related to the long-term infusion of high-concentration opioids.³⁴ The diagnosis is confirmed by MRI, but physical exam and history are imperative in making the initial diagnosis.

In cases of mild neurologic symptoms, a transition to saline infusion through the pump may allow the granuloma to absorb; more severe cases may require neurosurgical intervention.⁴⁷

Is your patient scheduled for an IT drug trial?

If a patient of yours is scheduled for an IT drug trial, ideally followed by pump implantation, microdosing—the practice of weaning the individual from oral opioids prior to the procedure so that very low doses of IT opioids will suffice—may play a role.^48,49 While this approach appears promising, however, there is little in the way of definitive evidence of efficacy.

CASE › Over time, Ms. G’s maintenance IT dose of morphine had to be slowly increased from 0.5 mg to 1 mg/d. At bimonthly visits with her FP, she consistently reports pain scores of 3 on a scale of 1 to 10. The patient’s function has returned to baseline, and she has minimal adverse effects. 

CORRESPONDENCE
Jessica Tsukanov, DO, Montefiore Medical Center, 3347 Steuben Avenue, Bronx, NY 10467; jtsukano@montefiore.org

A switch to hydromorphone 20 mg/d—the physician used the 5:1 morphine-to-hydromorphone conversion ratio, then decreased the dose by 50% to account for incomplete cross-tolerance—left Ms. G lethargic. In addition, her pain score rose to 5, and she began having difficulty swallowing the medication. Prior to the drug rotation, she was able to perform light tasks and was alert enough to interact with her family.

If Ms. G were your patient, what would be your next step?

By bypassing 
first-pass metabolism, intrathecal drug delivery provides greater pain relief at lower dosages and with fewer adverse effects than systemic delivery. Continuous intrathecal (IT) drug delivery systems have been in use for more than 30 years.¹ And, while IT administration of analgesia has become increasingly useful for patients with refractory chronic pain and spasticity, it remains an underutilized resource.² Delivered directly into the pre- and post-synaptic opioid receptors in the dorsal horn of the spinal cord, IT analgesia bypasses first-pass metabolism. The result: a higher rate of efficacy, with smaller dosages and fewer adverse effects than systemic delivery.¹

The drugs are delivered via a small battery-powered programmable pump that is implanted under the subcutaneous tissue of the abdomen and connected to a catheter tunneled to the site of spinal entry. The device must be refilled periodically—typically every one to 3 months—but this is not a difficult process. It can be done in an office setting or in the patient’s home by a specially trained visiting nurse.³

There is ample reason to consider this approach when systemic analgesics or antispasmodics fail to control pain or cause unacceptable adverse effects. So why isn’t it used more frequently? One factor may be that many primary care physicians—often the first practitioners called upon to manage these complicated cases—know too little about it.

Who is a potential candidate for IT analgesia? What medications can be administered via this route? What is the role of a family physician (FP) in coordinating and overseeing the care of a patient being treated with IT therapy? Our goals in writing this review are to address these questions.

Patient selection: Not just for cancer pain

Because of the invasive nature and high cost of implantation, intrathecal pumps are typically reserved for patients with a life expectancy of more than 6 months. FPs interested in referring patients for IT therapy have many factors to consider before consulting a pain specialist. Foremost among them are the different criteria for individuals with cancer-related pain and those with chronic nonmalignant pain.

IT analgesia for cancer pain has been shown to improve patients’ quality of life and potentially increase long-term survival due to a decrease in systemic toxicity.^4-6 An appropriate candidate is an individual who, like Ms. G, was initially responsive to systemic opioids but later developed refractory symptoms or intolerance.⁷ Because of the invasive nature and high cost of implantation, subcutaneous IT pumps are typically reserved for patients with a life expectancy of more than 6 months.⁷ But implantation may be considered for those with a shorter life expectancy if they have severe pain or cannot tolerate the adverse effects of systemic analgesia.

Noncancer pain is more complex

The use of IT analgesia in patients with chronic nonmalignant pain, such as failed back surgery syndrome, spasticity associated with multiple sclerosis, or diabetic neuropathy, is both more controversial and more complex. It is important for FPs to recognize the multidimensional nature of this type of pain, which may be complicated by physical, psychological, and behavioral factors, including the possibility of addiction.^8-11

Although IT analgesia is less subject to abuse and diversion than systemic opioids, the dependent relationship associated with a continuous delivery system makes risk stratification a necessity.¹² Psychological testing is commonly used to evaluate potential candidates for long-term IT analgesia.

Prior to placement, patients must have had a failed course of conservative pain management and have no surgical options, no medical contraindications (eg, spinal pathology or susceptibility to infection), and no evidence of active addiction.¹² A medication history is crucial, too, to identify use of anticoagulation therapy—a relative contraindication—as well as drug allergies and potential drug-drug interactions to guard against.³

An IT trial may be required

Psychological testing is commonly used to evaluate potential candidates for long-term intrathecal analgesia. It is common practice for patients to undergo an IT analgesia trial prior to implantation of a subcutaneous pump. This involves using an external pump to infuse the selected medication intrathecally and slowly titrating it according to symptoms for 2 to 3 days. During this time frame, the patient records his or her response; a reduction by more than half in VAS pain score is considered a success, indicating that the patient is an appropriate candidate for placement of the device.^3,13

Drug choices—a look at the evidence

The US Food and Drug Administration (FDA) has approved 3 medications for continuous IT delivery: morphine, ziconotide, and baclofen. But it is common practice to use alternative agents, such as other opioids, local anesthetics, or alpha 2-adrenergic agonists (TABLE).^3,14-34 

CASE  › Ms. G’s primary care physician referred her to a pain specialist, who thought she would benefit from IT analgesia. After a successful single-shot IT trial with 0.5 mg morphine, the patient underwent implantation.  The specialist chose morphine as the IT agent because of Ms. G’s history of successful pain relief with it, and because such a low dose was unlikely to be a problem for a patient with renal failure.

A month later, when she returned to the specialist to have the pump refilled, Ms. G reported a pain score of 3.

Opioids such as morphine exhibit a wider spread of analgesia when administered intrathecally, resulting in fewer adverse effects than systemic opioids.^13,35,36 The mu-opioid receptors in the dorsal horn of the spinal cord are the primary target of IT opioids.

In a multicenter randomized trial involving 200 cancer patients on opioids, Smith et al⁴ compared implantable IT drug delivery systems with comprehensive medical management. The mean VAS pain score in the IT group fell 52% vs a decline of 39% in the medical management group. 

The evidence supporting IT opioids for nonmalignant pain is not as strong. This may be due to inherent differences in pain mechanisms. In cancer pain, between 75% and 90% of pain is either nociceptive or mixed nociceptive-neuropathic; the etiology of noncancer pain is more variable.^37-39 

Although IT opioid therapy is associated with a lower incidence of adverse effects than systemic therapy, this route is not devoid of adverse effects. Opioids delivered intrathecally may still be associated with respiratory depression, constipation, urinary retention, nausea/vomiting, sweating, and hyperalgesia.³⁹ In addition, chronic opioid use suppresses the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis^14,40,41—a risk with long-term IT as well as systemic administration.¹⁴  Respiratory depression most commonly results from accidental overdosing, and patients must be monitored during initiation and dose escalation of IT opioid therapy.¹⁵

Local anesthetics. Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for patients with cancer^16-20 and noncancer pain.^21,22 Local anesthetics work via the blockade of voltage-gated sodium channels, interfering with neuron depolarization.¹⁷

Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for cancer and noncancer pain. A retrospective study in which patients with malignant pain and those with failed back surgery syndrome had bupivacaine added to their IT opioid solution found that the combination led to lower pain scores and a 23% reduction in opioid dosage.²⁰ In another retrospective review, researchers demonstrated that the coadministration of IT bupivacaine and an opioid decreased the rate of opioid dose escalation by 65% over the first year in patients with noncancer pain.²³

However, a double-blind randomized, crossover multicenter study found that in patients with chronic nonmalignant pain, the addition of bupivacaine to IT opioids failed to produce significant improvement in pain control compared with opioid use alone. Quality of life scores did improve, however, in the group receiving combination therapy.²⁴

Adverse effects of local anesthetics delivered intrathecally include numbness, paresthesias, weakness, bowel/bladder dysfunction, and neurotoxicity.^17,19,25  

Calcium channel blockers. Found in venom produced by the marine snail Conus magus, ziconotide blocks presynaptic N-type channels. It is the only calcium channel blocker used to manage chronic pain.²⁶ Several trials in patients with malignant and nonmalignant pain have shown a significant decrease in VAS pain scores compared with placebo.^25,26 In addition, a multicenter, double-blind placebo-controlled crossover study evaluating IT ziconotide for the treatment of refractory pain in 111 patients with cancer and AIDS found that the treatment group obtained significantly better pain relief than the controls (53% vs 17.5% using a VAS pain intensity score).²⁵ However, 31% of those in the treatment group experienced adverse effects, the most common of which were confusion, somnolence, and urinary retention.

Ziconotide has FDA approval only as monotherapy. But because of its high cost and adverse effect profile, it is mainly used in combination with other IT drugs.²⁷ Ziconotide increases the risk of suicide in patients with a history of depression.²⁸ The prevalence of adverse effects correlates with a higher dose, faster titration rate, and older age.^26,28

Alpha-2 adrenergic agonists. Clonidine is the only alpha-2 agonist with FDA approval for epidural use, with several studies supporting its off-label use in combination with IT therapy.^22,29 In a prospective open-label study evaluating combination IT therapy in patients with failed back surgery syndrome, 73% reported subjective ratings of good or excellent at 2-year follow-up.²² The most common adverse effects were sedation, hypotension, nausea, and dry mouth.

Gamma-aminobutyric acid (GABA) agonists. Baclofen, a GABA agonist with FDA approval for the treatment of spasticity, has been used intrathecally since the mid-1980s.³² Several studies have supported its effectiveness for this purpose.^30,42  Clinical studies have also found IT baclofen to be effective in treating conditions such as complex regional pain syndrome, central pain, and neuropathic pain secondary to failed back surgery syndrome.^31,32 In one randomized double-blind crossover trial, 7 women with complex regional pain syndrome were given bolus injections of baclofen or saline. Those treated with baclofen experienced a reduction in pain and regained function.³¹

In another trial—a double-blind placebo-controlled study of patients with multiple sclerosis and spinal cord injury comparing baclofen with placebo—those treated with baclofen showed significant reductions in dysesthetic and spasm-related pain.³² The most common adverse effects of baclofen are drowsiness, cognitive impairment, weakness, gastrointestinal complaints, and sexual dysfunction.³¹

Which patients and which drugs? An expert consensus

Due to the potential for inconsistent patient management and the use of therapies with anecdotal evidence, the Polyanalgesic Consensus Conference (PACC)—a panel of experts in IT therapy—convened in 2000, 2003, 2007, and 2011 to develop recommendations for IT therapy and an algorithm for drug selection. PACC’s list of chronic conditions for which IT should be considered includes axial low back pain, postherpetic neuralgia, spinal cord injury, spinal stenosis, pancreatitis, osteoporosis, compression fracture, and phantom limb pain, among others.

The algorithm contains separate arms for neuropathic, nociceptive, and mixed pain states. First-line agents for neuropathic pain include morphine, alone or combined with bupivacaine, and ziconotide. For nociceptive pain, morphine, hydromorphone, fentanyl, and ziconotide are all first-line agents; for mixed pain states, the appropriate choice should be based on the clinical scenario.³³

Overseeing IT pain management in primary care

Referring potential candidates for IT therapy to specialists in pain management is just the beginning. While patients typically return to the specialist for pump refills, it is important that they see their primary care physician regularly, as well. Vigilance is required of both the FP and the patient. Any sudden worsening in pain level or acute change in neurologic function must be reported to the pain specialist immediately. 

Adverse effects of medications are the most common complications

Kamran and Wright⁴³ performed a retrospective review of their practice’s Intrathecal Drug Delivery Systems database of 122 patients and found that adverse medication effects were most common, accounting for 77% of complications.

Catheter malfunctions were next, at 16%, followed by infections, at 5%.⁴³ In other studies, catheter-related complications were found to have an incidence of 15% to 25%.^44,45 Problems include kinking, breaking, leaking, and migration of the catheter. Advise patients to immediately contact their pain specialist for evaluation if they experience a sudden loss of, or change in, pain control.

Any sudden worsening in pain level or acute change in neurologic function must be reported immediately. Infectious complications, which occur infrequently, are usually limited to superficial wounds, although epidural abscesses and meningitis are possible.⁴⁶ Standard perioperative antibiotic administration helps to minimize the risk of infection. If a patient presents with signs and symptoms of an epidural abscess—back pain, fever, and variable neurologic deficits—emergent initiation of intravenous antibiotics is needed. Magnetic resonance imaging (MRI) with and without gadolinium should be obtained, as well.²²

Spinal damage. Although IT catheters are placed under fluoroscopic guidance, there is a risk of direct injury to the spinal cord; this is more common if the catheter is placed above the level of the conus medullaris. Damage to the spinal cord or exiting spinal nerves will manifest as pain, sensory loss, and/or weakness over a dermatomal distribution.⁴³

Neurologic sequelae, ranging from mild symptoms to paraplegia, can  result from the formation of a granuloma at the tip of the spinal catheter. A sudden increase in pain usually occurs prior to neurologic deterioration, thereby allowing for early detection and intervention.⁴⁷ Development of a granuloma appears to be related to the long-term infusion of high-concentration opioids.³⁴ The diagnosis is confirmed by MRI, but physical exam and history are imperative in making the initial diagnosis.

In cases of mild neurologic symptoms, a transition to saline infusion through the pump may allow the granuloma to absorb; more severe cases may require neurosurgical intervention.⁴⁷

Is your patient scheduled for an IT drug trial?

If a patient of yours is scheduled for an IT drug trial, ideally followed by pump implantation, microdosing—the practice of weaning the individual from oral opioids prior to the procedure so that very low doses of IT opioids will suffice—may play a role.^48,49 While this approach appears promising, however, there is little in the way of definitive evidence of efficacy.

CASE › Over time, Ms. G’s maintenance IT dose of morphine had to be slowly increased from 0.5 mg to 1 mg/d. At bimonthly visits with her FP, she consistently reports pain scores of 3 on a scale of 1 to 10. The patient’s function has returned to baseline, and she has minimal adverse effects. 

CORRESPONDENCE
Jessica Tsukanov, DO, Montefiore Medical Center, 3347 Steuben Avenue, Bronx, NY 10467; jtsukano@montefiore.org

A switch to hydromorphone 20 mg/d—the physician used the 5:1 morphine-to-hydromorphone conversion ratio, then decreased the dose by 50% to account for incomplete cross-tolerance—left Ms. G lethargic. In addition, her pain score rose to 5, and she began having difficulty swallowing the medication. Prior to the drug rotation, she was able to perform light tasks and was alert enough to interact with her family.

If Ms. G were your patient, what would be your next step?

By bypassing 
first-pass metabolism, intrathecal drug delivery provides greater pain relief at lower dosages and with fewer adverse effects than systemic delivery. Continuous intrathecal (IT) drug delivery systems have been in use for more than 30 years.¹ And, while IT administration of analgesia has become increasingly useful for patients with refractory chronic pain and spasticity, it remains an underutilized resource.² Delivered directly into the pre- and post-synaptic opioid receptors in the dorsal horn of the spinal cord, IT analgesia bypasses first-pass metabolism. The result: a higher rate of efficacy, with smaller dosages and fewer adverse effects than systemic delivery.¹

The drugs are delivered via a small battery-powered programmable pump that is implanted under the subcutaneous tissue of the abdomen and connected to a catheter tunneled to the site of spinal entry. The device must be refilled periodically—typically every one to 3 months—but this is not a difficult process. It can be done in an office setting or in the patient’s home by a specially trained visiting nurse.³

There is ample reason to consider this approach when systemic analgesics or antispasmodics fail to control pain or cause unacceptable adverse effects. So why isn’t it used more frequently? One factor may be that many primary care physicians—often the first practitioners called upon to manage these complicated cases—know too little about it.

Who is a potential candidate for IT analgesia? What medications can be administered via this route? What is the role of a family physician (FP) in coordinating and overseeing the care of a patient being treated with IT therapy? Our goals in writing this review are to address these questions.

Patient selection: Not just for cancer pain

Because of the invasive nature and high cost of implantation, intrathecal pumps are typically reserved for patients with a life expectancy of more than 6 months. FPs interested in referring patients for IT therapy have many factors to consider before consulting a pain specialist. Foremost among them are the different criteria for individuals with cancer-related pain and those with chronic nonmalignant pain.

IT analgesia for cancer pain has been shown to improve patients’ quality of life and potentially increase long-term survival due to a decrease in systemic toxicity.^4-6 An appropriate candidate is an individual who, like Ms. G, was initially responsive to systemic opioids but later developed refractory symptoms or intolerance.⁷ Because of the invasive nature and high cost of implantation, subcutaneous IT pumps are typically reserved for patients with a life expectancy of more than 6 months.⁷ But implantation may be considered for those with a shorter life expectancy if they have severe pain or cannot tolerate the adverse effects of systemic analgesia.

Noncancer pain is more complex

The use of IT analgesia in patients with chronic nonmalignant pain, such as failed back surgery syndrome, spasticity associated with multiple sclerosis, or diabetic neuropathy, is both more controversial and more complex. It is important for FPs to recognize the multidimensional nature of this type of pain, which may be complicated by physical, psychological, and behavioral factors, including the possibility of addiction.^8-11

Although IT analgesia is less subject to abuse and diversion than systemic opioids, the dependent relationship associated with a continuous delivery system makes risk stratification a necessity.¹² Psychological testing is commonly used to evaluate potential candidates for long-term IT analgesia.

Prior to placement, patients must have had a failed course of conservative pain management and have no surgical options, no medical contraindications (eg, spinal pathology or susceptibility to infection), and no evidence of active addiction.¹² A medication history is crucial, too, to identify use of anticoagulation therapy—a relative contraindication—as well as drug allergies and potential drug-drug interactions to guard against.³

An IT trial may be required

Psychological testing is commonly used to evaluate potential candidates for long-term intrathecal analgesia. It is common practice for patients to undergo an IT analgesia trial prior to implantation of a subcutaneous pump. This involves using an external pump to infuse the selected medication intrathecally and slowly titrating it according to symptoms for 2 to 3 days. During this time frame, the patient records his or her response; a reduction by more than half in VAS pain score is considered a success, indicating that the patient is an appropriate candidate for placement of the device.^3,13

Drug choices—a look at the evidence

The US Food and Drug Administration (FDA) has approved 3 medications for continuous IT delivery: morphine, ziconotide, and baclofen. But it is common practice to use alternative agents, such as other opioids, local anesthetics, or alpha 2-adrenergic agonists (TABLE).^3,14-34 

CASE  › Ms. G’s primary care physician referred her to a pain specialist, who thought she would benefit from IT analgesia. After a successful single-shot IT trial with 0.5 mg morphine, the patient underwent implantation.  The specialist chose morphine as the IT agent because of Ms. G’s history of successful pain relief with it, and because such a low dose was unlikely to be a problem for a patient with renal failure.

A month later, when she returned to the specialist to have the pump refilled, Ms. G reported a pain score of 3.

Opioids such as morphine exhibit a wider spread of analgesia when administered intrathecally, resulting in fewer adverse effects than systemic opioids.^13,35,36 The mu-opioid receptors in the dorsal horn of the spinal cord are the primary target of IT opioids.

In a multicenter randomized trial involving 200 cancer patients on opioids, Smith et al⁴ compared implantable IT drug delivery systems with comprehensive medical management. The mean VAS pain score in the IT group fell 52% vs a decline of 39% in the medical management group. 

The evidence supporting IT opioids for nonmalignant pain is not as strong. This may be due to inherent differences in pain mechanisms. In cancer pain, between 75% and 90% of pain is either nociceptive or mixed nociceptive-neuropathic; the etiology of noncancer pain is more variable.^37-39 

Although IT opioid therapy is associated with a lower incidence of adverse effects than systemic therapy, this route is not devoid of adverse effects. Opioids delivered intrathecally may still be associated with respiratory depression, constipation, urinary retention, nausea/vomiting, sweating, and hyperalgesia.³⁹ In addition, chronic opioid use suppresses the hypothalamic-pituitary-gonadal axis and the hypothalamic-pituitary-adrenal axis^14,40,41—a risk with long-term IT as well as systemic administration.¹⁴  Respiratory depression most commonly results from accidental overdosing, and patients must be monitored during initiation and dose escalation of IT opioid therapy.¹⁵

Local anesthetics. Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for patients with cancer^16-20 and noncancer pain.^21,22 Local anesthetics work via the blockade of voltage-gated sodium channels, interfering with neuron depolarization.¹⁷

Numerous studies have documented the favorable outcomes of combining local anesthetics with opioids for cancer and noncancer pain. A retrospective study in which patients with malignant pain and those with failed back surgery syndrome had bupivacaine added to their IT opioid solution found that the combination led to lower pain scores and a 23% reduction in opioid dosage.²⁰ In another retrospective review, researchers demonstrated that the coadministration of IT bupivacaine and an opioid decreased the rate of opioid dose escalation by 65% over the first year in patients with noncancer pain.²³

However, a double-blind randomized, crossover multicenter study found that in patients with chronic nonmalignant pain, the addition of bupivacaine to IT opioids failed to produce significant improvement in pain control compared with opioid use alone. Quality of life scores did improve, however, in the group receiving combination therapy.²⁴

Adverse effects of local anesthetics delivered intrathecally include numbness, paresthesias, weakness, bowel/bladder dysfunction, and neurotoxicity.^17,19,25  

Calcium channel blockers. Found in venom produced by the marine snail Conus magus, ziconotide blocks presynaptic N-type channels. It is the only calcium channel blocker used to manage chronic pain.²⁶ Several trials in patients with malignant and nonmalignant pain have shown a significant decrease in VAS pain scores compared with placebo.^25,26 In addition, a multicenter, double-blind placebo-controlled crossover study evaluating IT ziconotide for the treatment of refractory pain in 111 patients with cancer and AIDS found that the treatment group obtained significantly better pain relief than the controls (53% vs 17.5% using a VAS pain intensity score).²⁵ However, 31% of those in the treatment group experienced adverse effects, the most common of which were confusion, somnolence, and urinary retention.

Ziconotide has FDA approval only as monotherapy. But because of its high cost and adverse effect profile, it is mainly used in combination with other IT drugs.²⁷ Ziconotide increases the risk of suicide in patients with a history of depression.²⁸ The prevalence of adverse effects correlates with a higher dose, faster titration rate, and older age.^26,28

Alpha-2 adrenergic agonists. Clonidine is the only alpha-2 agonist with FDA approval for epidural use, with several studies supporting its off-label use in combination with IT therapy.^22,29 In a prospective open-label study evaluating combination IT therapy in patients with failed back surgery syndrome, 73% reported subjective ratings of good or excellent at 2-year follow-up.²² The most common adverse effects were sedation, hypotension, nausea, and dry mouth.

Gamma-aminobutyric acid (GABA) agonists. Baclofen, a GABA agonist with FDA approval for the treatment of spasticity, has been used intrathecally since the mid-1980s.³² Several studies have supported its effectiveness for this purpose.^30,42  Clinical studies have also found IT baclofen to be effective in treating conditions such as complex regional pain syndrome, central pain, and neuropathic pain secondary to failed back surgery syndrome.^31,32 In one randomized double-blind crossover trial, 7 women with complex regional pain syndrome were given bolus injections of baclofen or saline. Those treated with baclofen experienced a reduction in pain and regained function.³¹

In another trial—a double-blind placebo-controlled study of patients with multiple sclerosis and spinal cord injury comparing baclofen with placebo—those treated with baclofen showed significant reductions in dysesthetic and spasm-related pain.³² The most common adverse effects of baclofen are drowsiness, cognitive impairment, weakness, gastrointestinal complaints, and sexual dysfunction.³¹

Which patients and which drugs? An expert consensus

Due to the potential for inconsistent patient management and the use of therapies with anecdotal evidence, the Polyanalgesic Consensus Conference (PACC)—a panel of experts in IT therapy—convened in 2000, 2003, 2007, and 2011 to develop recommendations for IT therapy and an algorithm for drug selection. PACC’s list of chronic conditions for which IT should be considered includes axial low back pain, postherpetic neuralgia, spinal cord injury, spinal stenosis, pancreatitis, osteoporosis, compression fracture, and phantom limb pain, among others.

The algorithm contains separate arms for neuropathic, nociceptive, and mixed pain states. First-line agents for neuropathic pain include morphine, alone or combined with bupivacaine, and ziconotide. For nociceptive pain, morphine, hydromorphone, fentanyl, and ziconotide are all first-line agents; for mixed pain states, the appropriate choice should be based on the clinical scenario.³³

Overseeing IT pain management in primary care

Referring potential candidates for IT therapy to specialists in pain management is just the beginning. While patients typically return to the specialist for pump refills, it is important that they see their primary care physician regularly, as well. Vigilance is required of both the FP and the patient. Any sudden worsening in pain level or acute change in neurologic function must be reported to the pain specialist immediately. 

Adverse effects of medications are the most common complications

Kamran and Wright⁴³ performed a retrospective review of their practice’s Intrathecal Drug Delivery Systems database of 122 patients and found that adverse medication effects were most common, accounting for 77% of complications.

Catheter malfunctions were next, at 16%, followed by infections, at 5%.⁴³ In other studies, catheter-related complications were found to have an incidence of 15% to 25%.^44,45 Problems include kinking, breaking, leaking, and migration of the catheter. Advise patients to immediately contact their pain specialist for evaluation if they experience a sudden loss of, or change in, pain control.

Any sudden worsening in pain level or acute change in neurologic function must be reported immediately. Infectious complications, which occur infrequently, are usually limited to superficial wounds, although epidural abscesses and meningitis are possible.⁴⁶ Standard perioperative antibiotic administration helps to minimize the risk of infection. If a patient presents with signs and symptoms of an epidural abscess—back pain, fever, and variable neurologic deficits—emergent initiation of intravenous antibiotics is needed. Magnetic resonance imaging (MRI) with and without gadolinium should be obtained, as well.²²

Spinal damage. Although IT catheters are placed under fluoroscopic guidance, there is a risk of direct injury to the spinal cord; this is more common if the catheter is placed above the level of the conus medullaris. Damage to the spinal cord or exiting spinal nerves will manifest as pain, sensory loss, and/or weakness over a dermatomal distribution.⁴³

Neurologic sequelae, ranging from mild symptoms to paraplegia, can  result from the formation of a granuloma at the tip of the spinal catheter. A sudden increase in pain usually occurs prior to neurologic deterioration, thereby allowing for early detection and intervention.⁴⁷ Development of a granuloma appears to be related to the long-term infusion of high-concentration opioids.³⁴ The diagnosis is confirmed by MRI, but physical exam and history are imperative in making the initial diagnosis.

In cases of mild neurologic symptoms, a transition to saline infusion through the pump may allow the granuloma to absorb; more severe cases may require neurosurgical intervention.⁴⁷

Is your patient scheduled for an IT drug trial?

If a patient of yours is scheduled for an IT drug trial, ideally followed by pump implantation, microdosing—the practice of weaning the individual from oral opioids prior to the procedure so that very low doses of IT opioids will suffice—may play a role.^48,49 While this approach appears promising, however, there is little in the way of definitive evidence of efficacy.

CASE › Over time, Ms. G’s maintenance IT dose of morphine had to be slowly increased from 0.5 mg to 1 mg/d. At bimonthly visits with her FP, she consistently reports pain scores of 3 on a scale of 1 to 10. The patient’s function has returned to baseline, and she has minimal adverse effects. 

CORRESPONDENCE
Jessica Tsukanov, DO, Montefiore Medical Center, 3347 Steuben Avenue, Bronx, NY 10467; jtsukano@montefiore.org