• The aim of this study was to compare the effects of an implantable drug delivery system (IDDS with SynchroMed) with comprehensive medical management (CMM) on pain control, drug related toxicity and survival in patients with refractory cancer pain.
  
  
• The study involved 200 cancer patients with refractory pain and a pain visual analog (VAS) score of =5 despite 200mg morphine or the oral equivalent per day, who were randomised to treatment with either CMM or CMM plus IDDS.
  
  
• The main outcome measures were pain control (change in VAS) and change of composite toxicity from pain treatments as measured by the NCI Common Toxicity Criteria (CTC) after 4 weeks of treatment.

• The aim of this study was to compare the impact of pain and treatment toxicities on patient and family quality of life (QoL).
  
  
• This randomised study conducted at 21 centers in 5 countries, compared comprehensive medical management (CMM) versus CMM plus a programmable implantable drug delivery system (IDDS with SynchroMed) in 200 patients with pain not controlled by standard treatment.
  
  
• At randomization and at 4 week follow-up, pain was measured with a visual analog scale (VAS); pain medication toxicity with the NCI Common Toxicity Criteria (CTC); pain interference with patient quality of life using the Brief Pain Inventory (BPI); Caregiver QOL using the Family QOL questionnaire.

• The purpose of this multicentre, multinational study was to demonstrate the clinical effectiveness of the Medtronic SynchroMed intrathecal drug delivery system (IDDS) as a means of providing pain control therapy to patients with intractable cancer pain. The effect on side effects from opioids and non-opioid adjunctive (ADJ) pain medications was also analysed.
  
  
• 200 cancer patients (with pain not controlled by opioid doses ³200 mg/day of oral morphine or the equivalent) were randomly assigned to one of two groups: Comprehensive Medical Management (CMM) following standard guidelines (n=100) or IDDS with CMM (n=100).
  
  
• Pain was measured with a visual analogue scale (VAS) of 0-10 and pain medication toxicity with the NCI Common Toxicity Criteria (CTC). Calculation of morphine oral equivalent dose (MOED) allowed comparisons independent of the opioid dose used and route of administration.
  

• This study was one of the first studies to observe cancer patients in their homes with the aim of determining whether cancer patients were adhering to the 'around-the-clock' and 'as-needed' pain management regimens prescribed by their doctors.
  
  
• The randomised study involved 65 patients with baseline pain and evidence of bone metastases.
  
  
• Patients rated their level of pain intensity and recorded their pain medication intake on a daily basis. Adherence rates for opioid analgesics prescribed on an 'around-the-clock' and an 'as-needed' basis were calculated weekly.

Key points regarding medical equipment

• Almost 10-30% of cancer patients do not obtain relief from oral medication alone. In such patients, epidural and intrathecal administration of morphine and other medications can offer significant advantages.
  
  
• Concern over complications and infection has made some investigators reluctant to initiate intrathecal drug therapy. The epidural route of administration, used in earlier studies, often resulted in problems such as tissue reaction and fibrosis at the catheter site, impeding uniform diffusion during long-term use. In addition, the epidural route does not provide the significant dose-sparing effect seen with intrathecal drug delivery (IDD).
  
  
• In patients who received poor results with epidural or systemic administration of medications, IDD has been shown to keep the majority 'acceptably pain free' during treatment and can improve activity and sleep patterns. It has also demonstrated a low side effect profile. The feared complications of infection and meningitis have been rare.
  
  
• Percutaneous tunneled, exteriorized catheters (e.g. DuPen) can interfere with daily activities and hygiene, as well as cause local infection and catheter dislodgment.
  
  
• Implanted catheters with subcutaneous injection ports (e.g. Periplant, Port-a-Cath) have the advantage of greater freedom of patient movement and a possible decrease in infection. However, they require percutaneous injection for access and sometimes result in obstructed or perforated catheters.
  
  
• Totally implanted catheter systems with manually activated pumps (e.g. Algomed, Secor) can significantly improve pain scores and quality of life and have a low incidence of complications and mechanical malfunctions.
  
  
• Implanted continuous rate and programmable pumps (e.g. SynchroMed) offer reliability of infusion rate, freedom in patient movement and a low infection risk. Although initially expensive, the costs of an implanted infusion pump equal that of an exteriorized epidural catheter at 3 months, with financial advantage for implantation after 3 months.

Key points regarding intrathecal drugs

• Morphine and bupivacaine have been the most frequently used drugs for intrathecal infusion and their use has consistently yielded good results. However, a therapeutic deficit remains, primarily in the treatment of neuropathic cancer pain. Neuropathic pain patients have been found to require significantly higher drug doses.
  
  
• High doses of infused morphine are associated with tolerance and side effects of hyperalgesia, myoclonus and urinary retention. Bupivacaine potentiates and may act synergistically with morphine in the treatment of pain, leading to concern about tachyphylaxis. In addition, side effects of this anesthetic include paresthesia and paresis, as well as sphincter and gait disturbances and urinary retention.
  
  
• Consequently, recent research has focused on the use of novel compounds such as clonidine, midazolam, ketamine and SNX-111 in IDD to help treat patients with neuropathic cancer pain.
  
  
• Clonidine acts synergistically with opioids and is a powerful analgesic agent when used alone, especially in the treatment of neurogenic pain. Ketamine potentiates morphine analgesia and may prevent the development of opioid tolerance. Midazolam has antinociceptive and morphine-potentiating effects and has shown promising results with no signs of toxicity or tolerance. SNX-111 is notable for the lack of respiratory depression and minimal development of tolerance and may play a significant role in the treatment of neuropathic cancer pain.
  
  
• In addition to these new drug options, there are various catheter delivery systems from which to choose.
  

• This paper reviews the criteria for patient selection for neuraxial drug delivery, the technological systems available for neuraxial delivery and criteria for selection of the appropriate technology for the individual patient.
  
  
• In most patients, pain due to malignancy can be controlled by simple means. In some refractory cases however, the chronic delivery of analgesics to the epidural or subarachnoid space may be appropriate.
  
  
• The American Society of Anesthesiologists recommend that neuraxial drug infusions should be considered when adequate analgesia cannot be achieved with systemic methods of drug delivery or when intolerable side effects occur. Neuraxial drug delivery should be used:
  • when severe pain cannot be controlled with systemic drugs because of dose-limiting toxicity
  • when there is immediate need for a local anaesthetic (some types of neuropathic pain)
  • after failed neuroablation
  • when patient preference indicates its use
    
    
• Five types of neuraxial drug delivery systems are available: percutaneous catheter ± subcutaneous tunneling, implanted catheter with subcutaneous injection site (e.g. DuPen or Port-a-Cath), totally implanted catheter with implanted reservoir and manual pump (e.g. AlgoMed), totally implanted catheter with implanted infusion pump (e.g. Infusaid, Arrow M-3000, SynchroMed).
  
  
• Selection of a drug delivery system for an individual patient is based on several considerations including: patient life expectancy, cost effectiveness in light of limited life expectancy, choice of epidural vs subarachnoid route of administration, risk of infection, location of patient, type of pain, need for frequent patient-controlled bolusing.
  
  
• The location of the catheter is determined by the location and type of pain and the choice of analgesic.
  
  
• In general, it is assumed that percutaneous (tunneled) catheters are best suited for patients with limited life expectancy (<1 month) and implanted pump for patients with longer life expectancy. Given the difficulties in estimating length of survival, choosing the most appropriate drug delivery system may be challenging.
• Epidural and subarachnoid routes can be equally effective in managing intractable cancer pain. Expected duration of therapy guides choice of method. Catheter obstruction, fibrosis and loss of analgesic efficacy are well documented with long-term epidural administration, therefore subarachnoid administration would seem most appropriate if the patient's life expectancy is estimated to be greater than 3 to 6 months.
  
  
• Infections of neuraxial delivery systems may be classified as superficial (skin) infections, port or pump pocket infections, deep track infections (cellulitis) and epidural abscess or meningitis. Portal systems theoretically offer the advantage of a decreased risk of infection, whilst long-term use of exteriorized subarachnoid catheters is associated with a higher risk of infection.

• This was a retrospective study to report the analgesic effect of intrathecal morphine delivered via implanted infusion pumps, in patients with pain attributable to unresectable adenocarcinoma of the pancreas.
  
  
• Six patients underwent implantation with the Infusaid Implantable Pump System, and three with the Meditronic Drug Administration System.
  

• This paper reviews the use of intrathecal morphine pumps for the treatment of intractable cancer pain.
  
  
• Malignant pain affects 70-80% of terminal cancer patients. Most patients achieve adequate pain control with oral narcotics, NSAIDs and/or adjuvant medications. In a minority of cases, the opioid dose required for adequate pain relief causes unacceptable side effects such as extreme sedation. This makes the pain difficult to manage and can result in great suffering.
  
  
• Numerous studies have shown that intrathecal administration of morphine can be extremely effective and non-sedating and avoids many of the other undesirable side effects of oral/parenteral narcotics.
  
  
• Long-term morphine administration via an indwelling narcotic infusion pump provides safe, effective and prompt pain relief in pancreatic and other forms of cancer. Patients also report an increased level of activity and improved subjective overall quality of life.
  
  
• Studies indicate the importance of only considering patients for implantation who have achieved unequivocal relief of their pain with a pre-operative test dose.
  
  
• Intrathecal morphine administration has not typically been associated with sedation, neurological change, motor weakness, sensory or sympathetic dysfunction, significant change in vital signs or respiratory depression.
  
  
• Urinary retention affects around 67% of patients treated with intrathecal morphine, but usually resolves within days or weeks and prolonged bladder dysfunction is rare. pruritus is also common, affecting around 46% of patients. It usually responds to antihistamines, but may also be treated by naxolone reversal as it seems to result from morphine stimulation of dorsal root ganglion cells.
  
  
• The most serious risk of intrathecal morphine is respiratory depression, but this is extremely rare and occurs in <1% of patients. Patients should be monitored for 24 hours after injection or dose increase.
  
  
• Tolerance does develop to spinal opioids, but at a slower rate and lesser extent than with intravenous opioids. This may be of little significance in terminal cancer, due to limited life expectancy. It is also difficult to distinguish tolerance from increasing drug requirements due to disease progression.
  
  
• Local anesthetics may be added to intrathecal morphine preparations. This technique seems to improve pain control, but has significant risks of paresthesia, motor weakness and delayed urinary retention, which may not be reversible by discontinuing the infusion.
  
  
• A study has shown that adding ketamine to intrathecal morphine resulted in a decreased morphine requirement in malignant pain, without causing any increase in side effects. Animal studies suggest that ketamine reduces the development of morphine tolerance at spinal sites.
  
  
• Long-term epidural morphine has been used to control malignant pain. However, compared to intrathecal morphine, epidural morphine is less efficacious; tolerance develops more rapidly; side effects are more common and there is a greater risk of infection. Intrathecal delivery via an implanted subcutaneous pump poses less risk of infection than repeated injections into the system.
  
  
• The disadvantage of implanted subcutaneous pumps (e.g. Infusaid) is their cost. Consequently, it is important that patients be carefully selected for implantation based on the nature of their pain and their life expectancy. Efficacy is also dependent on participation by the patient and their family, so emotional stability and a supportive environment are crucial.

• This paper reviews the management of cancer pain poorly responsive to systemic opioid therapy.
  
  
• Systemic opioid therapy is widely accepted as the major approach to the treatment of cancer pain and optimal treatment provides adequate pain relief in as many as 90% of patients. More patients would derive benefit if undertreatment was to be eliminated, but a subgroup remains that does not respond adequately to an initial trial of systemic opioid therapy and must be considered for alternative analgesic strategies.
  
  
• These strategies can be categorized into four main groups:
  • 1. Opening the 'therapeutic window'
    More aggressive treatment of side effects may allow higher doses of the opioid required to improve analgesia (for example, the use of psychostimulant drugs to treat opioid-based somnolence and mental clouding).
  • 2. Opioid rotation
    There is remarkable variation in the responsiveness of individual patients to different opioids and the responsiveness of different patients to the same opioid. A poor response to one opioid does not predict an equally poor response to another. Sequential trials should be used to identify an opioid with a more favorable balance between analgesia and side effects.
  • 3. Pharmacological techniques that reduce the systemic opioid requirement
    Intraspinal opioid therapy or coadministration of a nonopioid analgesic may yield equal or better analgesia with less drug. The lower dosage may be associated with a more favorable balance between analgesia and side effects.
  • 4. Nonpharmacological or neurosurgical techniques
    A large number of nonpharmacologic analgesic approaches may result in a lower opioid requirement, for example, anesthesiology or surgical intervention, neurostimulation, rehabilitation measures, psychological therapy and complementary or alternative therapies.
    
    
• In the absence of comparative trials, the selection of a specific strategy depends on an informed risk/benefit evaluation based on information from a comprehensive clinical assessment.
  
  
• Several factors influence the use of intraspinal therapy in patients with poorly responsive pain including: the patient's medical, cognitive and psychosocial status, goals of care, pain characteristics, treatment limiting side effects during systemic therapy, drug delivery systems and economic issues.

• The study aimed to assess the risks and benefits of intrathecal analgesia in patients with terminal cancer.
  
  
• Patients were first given oral analgesia. If this failed or produced intolerable side-effects, subcutaneous administration was used. If this therapy failed, spinal, intrathecal, administration was used.